Heterocyclic compounds for cancer imaging and treatment and methods for their use

ABSTRACT

Compounds having a structure of Formula I:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, R3, R11a, R11b, R11c, R11d, X, n1, n2, and n3 are as defined herein, are provided. Uses of such compounds for modulating androgen receptor activity, imaging diagnostics in cancer and therapeutics, and methods for treatment of subjects in need thereof, including prostate cancer are also provided.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No.62/102,719 filed Jan. 23, 2015, the disclosure of which is hereinincorporated by reference in its entirety for all purposes.

STATEMENT OF GOVERNMENT INTEREST

This invention was made in part with government support under Grant No.2R01 CA105304 awarded by the National Cancer Institute. The UnitedStates Government has certain rights in this invention.

TECHNICAL FIELD

This invention generally relates to bisphenol-related compounds andtheir use for treatment of various indications. In particular theinvention relates to bisphenol ether compounds having novel heterocyclicgroups and their use for treatment of various cancers, for example allstages of prostate cancer, including androgen dependent, androgensensitive and castration-resistant prostate cancers. This invention alsorelates to bisphenol-related compounds and their use for modulatingandrogen receptor (AR) activity.

This invention further relates to radiolabeled bisphenol-relatedcompounds and their use in methods for imaging the prostate gland. Forexample, in certain embodiments the compounds are useful for imagingbenign prostate diseases such as benign prostate hyperplasia. In otherembodiments, the compounds are useful for imaging cancerous prostatediseases, such as prostate cancer tumors. In certain embodiments theinvention relates to radioactive ¹²³I compounds and their use as animaging tool in prostate cancer and benign prostate diseases. Thedisclosed compounds find utility in any number of imaging applications,including imaging of androgen receptor (AR) splice variants in prostatecancers, including all stages and androgen dependent, androgen-sensitiveand castration-resistant prostate cancers (also referred to as hormonerefractory, androgen-independent, androgen deprivation resistant,androgen ablation resistant, androgen depletion-independent,castration-recurrent, anti-androgen-recurrent).

DESCRIPTION OF THE RELATED ART

Androgens mediate their effects through the androgen receptor (AR).Androgens play a role in a wide range of developmental and physiologicalresponses and are involved in male sexual differentiation, maintenanceof spermatogenesis, and male gonadotropin regulation (R. K. Ross, G. A.Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E.Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355-361(1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N. Tanji, K.Aoki & M. Yokoyama, Arch Androl 47, 1-7 (2001)). Several lines ofevidence show that androgens are associated with the development ofprostate carcinogenesis. Firstly, androgens induce prostaticcarcinogenesis in rodent models (R. L. Noble, Cancer Res 37, 1929-1933(1977); R. L. Noble, Oncology 34, 138-141 (1977)) and men receivingandrogens in the form of anabolic steroids have a higher incidence ofprostate cancer (J. T. Roberts & D. M. Essenhigh, Lancet 2, 742 (1986);J. A. Jackson, J. Waxman & A. M. Spiekerman, Arch Intern Med 149,2365-2366 (1989); P. D. Guinan, W. Sadoughi, H. Alsheik, R. J. Ablin, D.Alrenga & I. M. Bush, Am J Surg 131, 599-600 (1976)). Secondly, prostatecancer does not develop if humans or dogs are castrated before puberty(J. D. Wilson & C. Roehrborn, J Clin Endocrinol Metab 84, 4324-4331(1999); G. Wilding, Cancer Surv 14, 113-130 (1992)). Castration of adultmales causes involution of the prostate and apoptosis of prostaticepithelium while eliciting no effect on other male external genitalia(E. M. Bruckheimer & N. Kyprianou, Cell Tissue Res 301, 153-162 (2000);J. T. Isaacs, Prostate 5, 545-557 (1984)). This dependency on androgensprovides the underlying rationale for treating prostate cancer withchemical or surgical castration (androgen ablation).

Androgens also play a role in female diseases such as polycystic ovarysyndrome as well as cancers. One example is ovarian cancer whereelevated levels of androgens are associated with an increased risk ofdeveloping ovarian cancer (K. J. Helzlsouer, A. J. Alberg, G. B. Gordon,C. Longcope, T. L. Bush, S. C. Hoffman & G. W. Comstock, JAMA 274,1926-1930 (1995); R. J. Edmondson, J. M. Monaghan & B. R. Davies, Br JCancer 86, 879-885 (2002)). The AR has been detected in a majority ofovarian cancers (H. A. Risch, J Natl Cancer Inst 90, 1774-1786 (1998);B. R. Rao & B. J. Slotman, Endocr Rev 12, 14-26 (1991); G. M. Clinton &W. Hua, Crit Rev Oncol Hematol 25, 1-9 (1997)), whereas estrogenreceptor-alpha (ERa) and the progesterone receptor are detected in lessthan 50% of ovarian tumors.

The only effective treatment available for advanced prostate cancer isthe withdrawal of androgens which are essential for the survival ofprostate epithelial cells. Androgen ablation therapy causes a temporaryreduction in tumor burden concomitant with a decrease in serumprostate-specific antigen (PSA). Unfortunately prostate cancer caneventually grow again in the absence of testicular androgens(castration-resistant disease) (Huber et al 1987 Scand J. Urol Nephrol.104, 33-39). Castration-resistant prostate cancer is biochemicallycharacterized before the onset of symptoms by a rising titre of serumPSA (Miller et al 1992 J. Urol. 147, 956-961). Once the disease becomescastration-resistant most patients succumb to their disease within twoyears.

The AR has distinct functional domains that include the carboxy-terminalligand-binding domain (LBD), a DNA-binding domain (DBD) comprising twozinc finger motifs, and an N-terminus domain (NTD) that contains one ormore transcriptional activation domains. Binding of androgen (ligand) tothe LBD of the AR results in its activation such that the receptor caneffectively bind to its specific DNA consensus site, termed the androgenresponse element (ARE), on the promoter and enhancer regions of“normally” androgen regulated genes, such as PSA, to initiatetranscription. The AR can be activated in the absence of androgen bystimulation of the cAMP-dependent protein kinase (PKA) pathway, withinterleukin-6 (IL-6) and by various growth factors (Culig et al 1994Cancer Res. 54, 5474-5478; Nazareth et al 1996 J. Biol. Chem. 271,19900-19907; Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 AJ. Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277,38087-38094). The mechanism of ligand-independent transformation of theAR has been shown to involve: 1) increased nuclear AR protein suggestingnuclear translocation; 2) increased AR/ARE complex formation; and 3) theAR-NTD (Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J.Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277,38087-38094). The AR can be activated in the absence of testicularandrogens by alternative signal transduction pathways incastration-resistant disease, which is consistent with the finding thatnuclear AR protein is present in secondary prostate cancer tumors (Kimet al 2002 Am. J. Pathol. 160, 219-226; and van der Kwast et al 1991Inter. J. Cancer 48, 189-193).

Available inhibitors of the AR include nonsteroidal antiandrogens suchas bicalutamide (Casodex™), nilutamide, flutamide, enzulutamide andinvestigational drug ARN-509 and steroidal antiandrogens, such ascyproterone acetate. These antiandrogens target the LBD of the AR andpredominantly fail presumably due to poor affinity and mutations thatlead to activation of the AR by these same antiandrogens (Taplin, M. E.,Bubley, G. J., Kom Y. J., Small E. J., Uptonm M., Rajeshkumarm B., BalkmS. P., Cancer Res., 59, 2511-2515 (1999)). These antiandrogens wouldalso have no effect on the recently discovered AR splice variants thatlack the ligand-binding domain (LBD) to result in a constitutivelyactive receptor which promotes progression of castration recurrentprostate cancer (Dehm S M, Schmidt L J, Heemers H V, Vessella R L,Tindall D J., Cancer Res 68, 5469-77, 2008; Guo Z, Yang X, Sun F, JiangR, Linn D E, Chen H, Chen H, Kong X, Melamed J, Tepper C G, Kung H J,Brodie A M, Edwards J, Qiu Y., Cancer Res. 69, 2305-13, 2009; Hu et al2009 Cancer Res. 69, 16-22; Sun et al 2010 J Clin Invest. 2010 120,2715-30).

Conventional therapy has concentrated on androgen-dependent activationof the AR through its C-terminal domain. Studies developing antagoniststo the AR have concentrated on the C-terminus and specifically: 1) theallosteric pocket and AF-2 activity (Estébanez-Perpiñá et al 2007, PNAS104, 16074-16079); 2) in silico “drug repurposing” procedure foridentification of nonsteroidal antagonists (Bisson et al 2007, PNAS 104,11927-11932); and coactivator or corepressor interactions (Chang et al2005, Mol Endocrinology 19, 2478-2490; Hur et al 2004, PLoS Biol 2,E274; Estébanez-Perpiñá et al 2005, JBC 280, 8060-8068; He et al 2004,Mol Cell 16, 425-438).

The AR-NTD is also a target for drug development (e.g. WO 2000/001813),since the NTD contains Activation-Function-1 (AF-1) which is theessential region required for AR transcriptional activity (Jenster et al1991. Mol Endocrinol. 5, 1396-404). The AR-NTD importantly plays a rolein activation of the AR in the absence of androgens (Sadar, M. D. 1999J. Biol. Chem. 274, 7777-7783; Sadar M D et al 1999 Endocr Relat Cancer.6, 487-502; Ueda et al 2002 J. Biol. Chem. 277, 7076-7085; Ueda 2002 J.Biol. Chem. 277, 38087-38094; Blaszczyk et al 2004 Clin Cancer Res. 10,1860-9; Dehm et al 2006 J Biol Chem. 28, 27882-93; Gregory et al 2004 JBiol Chem. 279, 7119-30). The AR-NTD is important in hormonalprogression of prostate cancer as shown by application of decoymolecules (Quayle et al 2007, Proc Natl Acad Sci USA. 104, 1331-1336).

While the crystal structure has been resolved for the AR C-terminus LBD,this has not been the case for the NTD due to its high flexibility andintrinsic disorder in solution (Reid et al 2002 J. Biol. Chem. 277,20079-20086) thereby hampering virtual docking drug discoveryapproaches. Compounds that modulate AR include the bis-phenol compoundsdisclosed in published PCT Nos: WO 2010/000066, WO 2011/082487; WO2011/082488; WO 2012/145330; WO 2012/139039; WO 2012/145328; WO2013/028572; WO 2013/028791; and WO 2014/179867, which are herebyincorporated by reference in their entireties, to the British ColumbiaCancer Agency Branch and The University of British Columbia.

In addition to compounds which modulate AR, compounds and methods forimaging the prostate are useful research, diagnostic and prognostictools. Such compounds are useful in many applications, including imagingof benign and/or malignant prostate cells and tissue. In this regard,positron emission tomography (PET) is an often used imaging techniquefor non-invasive identification of pathological state and tumors. In PETimaging, the distribution of a radioisotope (e.g., ¹⁸F) in the body canbe determined. Thus incorporating ¹⁸F into compounds which concentratein tumor sites (see e.g., WO 2013/028791) offers potential fordiagnosis, staging, and monitoring treatment of cancers. However,improved methods for imaging are needed, for example methods whichemploy ¹²³I and single photon emission coupled tomography (SPECT)techniques have potential to improve methods for imaging AR-rich tissuessuch as the benign prostate, and in particular prostate cancers and ARsplice variants in castrate recurrent prostate cancers.

While significant advances have been made in this field, there remains aneed for improved imaging agents. In particular, methods and compoundssuitable for imaging benign and malignant prostate tissues and cells areneeded. The present invention fulfills these needs, and provides otherrelated advantages.

BRIEF SUMMARY

Some embodiments of the compounds described herein can be used fordiagnostic purposes to investigate diseases of the prostate, includingcancer. In particular embodiments, the compounds are useful for imagingdiagnostics in cancer. In some embodiments, such imaging allows for thedetection and/or location of cancer sites (e.g., tumor sites).Furthermore, these compounds can be used individually or as part of akit for such purposes.

The present disclosure is based in part on the surprising discovery thatthe compounds described herein, can be used to modulate AR activityeither in vivo or in vitro for both research and therapeutic uses.Accordingly, embodiments of the compounds are useful for imaging theprostate. The imaging can be for any number of diagnostic purposes. Forexample, in certain embodiments the compounds are useful for imagingbenign prostate cancer diseases. In other embodiments, the compoundsfind utility for imaging of certain cancers, including prostate cancersince certain embodiments of the compounds localize in prostate tumorsites. Other imaging agents are androgen mimics; however, in oneembodiment, the compounds are useful for imaging AR splice variants orany AR species (i.e., those mutated in other domains or regions). The ARcan be mammalian. For example, the AR can be human. The prostate cancercan be castration-resistant prostate cancer. The prostate cancer can beandrogen-dependent prostate cancer.

In accordance with one embodiment, there is provided a compound having astructure of Formula I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein R¹, R², R³, R^(11a), R^(11b), R^(11c), R^(11d), X, n¹, n² and n³are as defined herein. In one embodiment, the compound of Formula (I)comprising at least one F, Cl, Br, I, ¹⁸F or ¹²³I moiety, are provided.

In other embodiments pharmaceutical compositions comprising a compoundof Formula (I) are provided. Methods employing such pharmaceuticalcompositions for imaging cancer are also provided. Methods formodulating AR activity employing the present compounds andpharmaceutical compositions are also provided.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a ¹H NMR spectrum of Compound i-H.

FIG. 2 is a ¹³C NMR spectrum of Compound i-H.

FIG. 3 is a ¹H NMR spectrum of Compound ii-H.

FIG. 4 is a ¹³C NMR spectrum of Compound ii-H.

FIG. 5 is a ¹H NMR spectrum of Compound 1a.

FIG. 6 is a ¹³C NMR spectrum of Compound 1a.

FIG. 7 is a ¹H NMR spectrum of Compound 25a.

FIG. 8 is a ¹³C NMR spectrum of Compound 25a.

FIG. 9 is a ¹H NMR spectrum of Compound i-I.

FIG. 10 is a ¹³C NMR spectrum of Compound i-I.

FIG. 11 is a ¹H NMR spectrum of Compound ii-I.

FIG. 12 is a ¹³C NMR spectrum of Compound ii-I.

FIG. 13 is a ¹H NMR spectrum of Compound 4a.

FIG. 14 is a ¹³C NMR spectrum of Compound 5a.

FIG. 15 is a ¹H NMR spectrum of Compound 28a.

FIG. 16 is a ¹³C NMR spectrum of Compound 28a.

FIG. 17 is a ¹H NMR spectrum of Compound 13.

DETAILED DESCRIPTION I. Definitions

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention canbe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment. Thus, the appearances of the phrases “in one embodiment” or“in an embodiment” in various places throughout this specification arenot necessarily all referring to the same embodiment. Furthermore, theparticular features, structures, or characteristics can be combined inany suitable manner in one or more embodiments. Also, as used in thisspecification and the appended claims, the singular forms “a,” “an,” and“the” include plural referents unless the content clearly dictatesotherwise. It should also be noted that the term “or” is generallyemployed in its sense including “and/or” unless the content clearlydictates otherwise.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” or “alkyl group” refers to a fully saturated, straight orbranched hydrocarbon chain radical having from one to twelve carbonatoms, and which is attached to the rest of the molecule by a singlebond. Alkyls comprising any number of carbon atoms from 1 to 12 areincluded. An alkyl comprising up to 12 carbon atoms is a C₁-C₁₂ alkyl,an alkyl comprising up to 10 carbon atoms is a C₁-C₁₀ alkyl, an alkylcomprising up to 6 carbon atoms is a C₁-C₆ alkyl and an alkyl comprisingup to 5 carbon atoms is a C₁-C₅ alkyl. A C₁-C₅ alkyl includes C₅ alkyls,C₄ alkyls, C₃ alkyls, C₂ alkyls and C₁ alkyl (i.e., methyl). A C₁-C₆alkyl includes all moieties described above for C₁-C₅ alkyls but alsoincludes C₆ alkyls. A C₁-C₁₀ alkyl includes all moieties described abovefor C₁-C₅ alkyls and C₁-C₆ alkyls, but also includes C₇, C₈, C₉ and C₁₀alkyls. Similarly, a C₁-C₁₂ alkyl includes all the foregoing moieties,but also includes C₁₁ and C₁₂ alkyls. Non-limiting examples of C₁-C₁₂alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl,i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless statedotherwise specifically in the specification, an alkyl group can beoptionally substituted.

“Alkylene” or “alkylene chain” refers to a fully saturated, straight orbranched divalent hydrocarbon chain radical, and having from one totwelve carbon atoms. Non-limiting examples of C₁-C₁₂ alkylene includemethylene, ethylene, propylene, n-butylene, ethenylene, propenylene,n-butenylene, propynylene, n-butynylene, and the like. The alkylenechain is attached to the rest of the molecule through a single bond andto the radical group through a single bond. The points of attachment ofthe alkylene chain to the rest of the molecule and to the radical groupcan be through one carbon or any two carbons within the chain. Unlessstated otherwise specifically in the specification, an alkylene chaincan be optionally substituted.

“Alkenyl” or “alkenyl group” refers to a straight or branchedhydrocarbon chain radical having from two to twelve carbon atoms, andhaving one or more carbon-carbon double bonds. Each alkenyl group isattached to the rest of the molecule by a single bond. Alkenyl groupcomprising any number of carbon atoms from 2 to 12 are included. Analkenyl group comprising up to 12 carbon atoms is a C₂-C₁₂ alkenyl, analkenyl comprising up to 10 carbon atoms is a C₂-C₁₀ alkenyl, an alkenylgroup comprising up to 6 carbon atoms is a C₂-C₆ alkenyl and an alkenylcomprising up to 5 carbon atoms is a C₂-C₅ alkenyl. A C₂-C₅ alkenylincludes C₅ alkenyls, C₄ alkenyls, C₃ alkenyls, and C₂ alkenyls. A C₂-C₆alkenyl includes all moieties described above for C₂-C₅ alkenyls butalso includes C₆ alkenyls. A C₂-C₁₀ alkenyl includes all moietiesdescribed above for C₂-C₅ alkenyls and C₂-C₆ alkenyls, but also includesC₇, C₈, C₉ and C₁₀ alkenyls. Similarly, a C₂-C₁₂ alkenyl includes allthe foregoing moieties, but also includes C₁₁ and C₁₂ alkenyls.Non-limiting examples of C₂-C₁₂ alkenyl include ethenyl (vinyl),1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl,1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl,7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl,6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl,4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl,1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl,6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl,1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl,6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and11-dodecenyl. Unless stated otherwise specifically in the specification,an alkyl group can be optionally substituted.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain radical, having from two to twelve carbonatoms, and having one or more carbon-carbon double bonds. Non-limitingexamples of C₂-C₁₂ alkenylene include ethene, propene, butene, and thelike. The alkenylene chain is attached to the rest of the moleculethrough a single bond and to the radical group through a single bond.The points of attachment of the alkenylene chain to the rest of themolecule and to the radical group can be through one carbon or any twocarbons within the chain. Unless stated otherwise specifically in thespecification, an alkenylene chain can be optionally substituted.

“Alkynyl” or “alkynyl group” refers to a straight or branchedhydrocarbon chain radical having from two to twelve carbon atoms, andhaving one or more carbon-carbon triple bonds. Each alkynyl group isattached to the rest of the molecule by a single bond. Alkynyl groupcomprising any number of carbon atoms from 2 to 12 are included. Analkynyl group comprising up to 12 carbon atoms is a C₂-C₁₂ alkynyl, analkynyl comprising up to 10 carbon atoms is a C₂-C₁₀ alkynyl, an alkynylgroup comprising up to 6 carbon atoms is a C₂-C₆ alkynyl and an alkynylcomprising up to 5 carbon atoms is a C₂-C₅ alkynyl. A C₂-C₅ alkynylincludes C₅ alkynyls, C₄ alkynyls, C₃ alkynyls, and C₂ alkynyls. A C₂-C₆alkynyl includes all moieties described above for C₂-C₅ alkynyls butalso includes C₆ alkynyls. A C₂-C₁₀ alkynyl includes all moietiesdescribed above for C₂-C₅ alkynyls and C₂-C₆ alkynyls, but also includesC₇, C₈, C₉ and C₁₀ alkynyls. Similarly, a C₂-C₁₂ alkynyl includes allthe foregoing moieties, but also includes C₁₁ and C₁₂ alkynyls.Non-limiting examples of C₂-C₁₂ alkenyl include ethynyl, propynyl,butynyl, pentynyl and the like. Unless stated otherwise specifically inthe specification, an alkyl group can be optionally substituted.

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain radical, having from two to twelve carbonatoms, and having one or more carbon-carbon triple bonds. Non-limitingexamples of C₂-C₁₂ alkynylene include ethynylene, propargylene and thelike. The alkynylene chain is attached to the rest of the moleculethrough a single bond and to the radical group through a single bond.The points of attachment of the alkynylene chain to the rest of themolecule and to the radical group can be through one carbon or any twocarbons within the chain. Unless stated otherwise specifically in thespecification, an alkynylene chain can be optionally substituted.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl, alkenyl or alknyl radical as defined above containing one totwelve carbon atoms. Unless stated otherwise specifically in thespecification, an alkoxy group can be optionally substituted.

“Alkylamino” refers to a radical of the formula —NHR_(a) or —NR_(a)R_(a)where each R_(a) is, independently, an alkyl, alkenyl or alkynyl radicalas defined above containing one to twelve carbon atoms. Unless statedotherwise specifically in the specification, an alkylamino group can beoptionally substituted.

“Alkylcarbonyl” refers to the —C(═O)R_(a) moiety, wherein R_(a) is analkyl, alkenyl or alkynyl radical as defined above. A non-limitingexample of an alkyl carbonyl is the methyl carbonyl (“acetal”) moiety.Alkylcarbonyl groups can also be referred to as “Cw-Cz acyl” where w andz depicts the range of the number of carbon in R_(a), as defined above.For example, “C1-C₁₀ acyl” refers to alkylcarbonyl group as definedabove, where R_(a) is C₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, or C₁-C₁₀ alkynylradical as defined above. Unless stated otherwise specifically in thespecification, an alkyl carbonyl group can be optionally substituted.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical can be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which can include fused or bridgedring systems. Aryl radicals include, but are not limited to, arylradicals derived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, fluoranthene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene,phenanthrene, pleiadene, pyrene, and triphenylene. Unless statedotherwise specifically in the specification, the term “aryl” is meant toinclude aryl radicals that are optionally substituted.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene, alkenylene or alkynylene group as defined above and R_(c)is one or more aryl radicals as defined above, for example, benzyl,diphenylmethyl and the like. Unless stated otherwise specifically in thespecification, an aralkyl group can be optionally substituted.

“Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a ringsstructure, wherein the atoms which form the ring are each carbon.Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring.Carbocyclic rings include aryls and cycloalkyl. cycloalkenyl andcycloalkynyl as defined herein. Unless stated otherwise specifically inthe specification, a carbocyclyl group can be optionally substituted.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclicfully saturated hydrocarbon radical consisting solely of carbon andhydrogen atoms, which can include fused or bridged ring systems, havingfrom three to twenty carbon atoms, preferably having from three to tencarbon atoms, and which is attached to the rest of the molecule by asingle bond. Monocyclic cycloalkyl radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic cycloalkyl radicals include, for example,adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl,and the like. Unless otherwise stated specifically in the specification,a cycloalkyl group can be optionally substituted.

“Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having one or more carbon-carbon double bonds, which can include fusedor bridged ring systems, having from three to twenty carbon atoms,preferably having from three to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond. Monocyclic cycloalkenylradicals include, for example, cyclopentenyl, cyclohexenyl,cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenylradicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like.Unless otherwise stated specifically in the specification, acycloalkenyl group can be optionally substituted.

“Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having one or more carbon-carbon triple bonds, which can include fusedor bridged ring systems, having from three to twenty carbon atoms,preferably having from three to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond. Monocyclic cycloalkynylradicals include, for example, cycloheptynyl, cyclooctynyl, and thelike. Unless otherwise stated specifically in the specification, acycloalkynyl group can be optionally substituted.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)—Rd whereR_(b) is an alkylene, alkenylene, or alkynylene group as defined aboveand R_(d) is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as definedabove. Unless stated otherwise specifically in the specification, acycloalkylalkyl group can be optionally substituted.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. Unless stated otherwise specifically in the specification, ahaloalkyl group can be optionally substituted.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless statedotherwise specifically in the specification, a haloalkenyl group can beoptionally substituted.

“Haloalkynyl” refers to an alkynyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwisespecifically in the specification, a haloalkenyl group can be optionallysubstituted.

“Heterocyclyl,” “heterocyclic ring” or “heterocycle” refers to a stable3- to 20-membered non-aromatic ring radical which consists of two totwelve carbon atoms and from one to six heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur. Heterocyclycl orheterocyclic rings include heteroaryls as defined below. Unless statedotherwise specifically in the specification, the heterocyclyl radicalcan be a monocyclic, bicyclic, tricyclic or tetracyclic ring system,which can include fused or bridged ring systems; and the nitrogen,carbon or sulfur atoms in the heterocyclyl radical can be optionallyoxidized; the nitrogen atom can be optionally quaternized; and theheterocyclyl radical can be partially or fully saturated. Examples ofsuch heterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocyclyl group can be optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. Unless stated otherwisespecifically in the specification, a N-heterocyclyl group can beoptionally substituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)—R_(c)where R_(b) is an alkylene, alkenylene, or alkynylene chain as definedabove and Re is a heterocyclyl radical as defined above, and if theheterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl canbe attached to the alkyl, alkenyl, alkynyl radical at the nitrogen atom.Unless stated otherwise specifically in the specification, aheterocyclylalkyl group can be optionally substituted.

“Heteroaryl” refers to a 5- to 20-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical can be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which can include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical can be optionally oxidized; the nitrogen atom can be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group can be optionallysubstituted.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. Unless stated otherwise specifically inthe specification, an N-heteroaryl group can be optionally substituted.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)—R_(f) whereR_(b) is an alkylene, alkenylene, or alkynylene chain as defined aboveand R_(f) is a heteroaryl radical as defined above. Unless statedotherwise specifically in the specification, a heteroarylalkyl group canbe optionally substituted.

“¹²³I” refers to the radioactive isotope of iodine having atomic mass123. The compounds of Formula I can comprise at least one ¹²³I moiety.Throughout the present application, where structures depict a ¹²³Imoiety at a certain position it is meant that the I moiety at thisposition is enriched for ¹²³I. In other words, the compounds containmore than the natural abundance of ¹²³I at the indicated position(s). Itis not required that the compounds comprise 100% ¹²³I at the indicatedpositions, provided ¹²³I is present in more than the natural abundance.Typically the ¹²³I isotope is enriched to greater than 50%, greater than60%, greater than 70%, greater than, 80% or greater than 90%, relativeto ¹²⁷I.

“¹⁸F” refers to the radioactive isotope of fluorine having atomic mass18. “F” or “¹⁹F” refers to the abundant, non-radioactive fluorineisotope having atomic mass 19. The compounds of Formula I can compriseat least one ¹⁸F moiety. Throughout the present application, wherestructures depict a ¹⁸F moiety at a certain position it is meant thatthe F moiety at this position is enriched for ¹⁸F. In other words, thecompounds contain more than the natural abundance of ¹⁸F at theindicated position(s). It is not required that the compounds comprise100% ¹⁸F at the indicated positions, provided ¹⁸F is present in morethan the natural abundance. Typically the ¹⁸F isotope is enriched togreater than 50%, greater than 60%, greater than 70%, greater than 80%or greater than 90%, relative to ¹⁹F.

“Thioalkyl” refers to a radical of the formula —SR_(a) where R_(a) is analkyl, alkenyl, or alkynyl radical as defined above containing one totwelve carbon atoms. Unless stated otherwise specifically in thespecification, a thioalkyl group can be optionally substituted.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy,alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl,cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atomis replaced by a bond to a non-hydrogen atoms such as, but not limitedto: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groupssuch as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atomin groups such as thiol groups, thioalkyl groups, sulfone groups,sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such asamines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines,diarylamines, N-oxides, imides, and enamines; a silicon atom in groupssuch as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilylgroups, and triarylsilyl groups; and other heteroatoms in various othergroups. “Substituted” also means any of the above groups in which one ormore hydrogen atoms are replaced by a higher-order bond (e.g., a double-or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl,carboxyl, and ester groups; and nitrogen in groups such as imines,oximes, hydrazones, and nitriles. For example, “substituted” includesany of the above groups in which one or more hydrogen atoms are replacedwith —NR_(g)R_(h), —NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h),—NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g),—SR_(g), —SOR_(g), —SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), and—SO₂NR_(g)R_(h). “Substituted also means any of the above groups inwhich one or more hydrogen atoms are replaced with —C(═O)R_(g),—C(═O)OR_(g), —C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), —CH₂SO₂NR_(g)R_(h). Inthe foregoing, R_(g) and R_(h) are the same or different andindependently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl,cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl,N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/orheteroarylalkyl. “Substituted” further means any of the above groups inwhich one or more hydrogen atoms are replaced by a bond to an amino,cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl,alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl,haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl,heteroaryl, N-heteroaryl and/or heteroarylalkyl group. In addition, eachof the foregoing substituents can also be optionally substituted withone or more of the above substituents.

As used herein, the symbol

(hereinafter can be referred to as “a point of attachment bond”) denotesa bond that is a point of attachment between two chemical entities, oneof which is depicted as being attached to the point of attachment bondand the other of which is not depicted as being attached to the point ofattachment bond. For example,

indicates that the chemical entity “XY” is bonded to another chemicalentity via the point of attachment bond. Furthermore, the specific pointof attachment to the non-depicted chemical entity can be specified byinference. For example, the compound CH₃—R³, wherein R³ is H or

infers that when R³ is “XY”, the point of attachment bond is the samebond as the bond by which is depicted as being bonded to CH₃.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring can be replaced with anitrogen atom.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products can resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising administering a compound of thisinvention to a mammal for a period of time sufficient to yield ametabolic product thereof. Such products are typically identified byadministering a radiolabelled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein, a “subject” can be a human, non-human primate, mammal,rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like. Thesubject can be suspected of having or at risk for having a cancer, suchas prostate cancer, breast cancer, ovarian cancer, salivary glandcarcinoma, or endometrial cancer, or suspected of having or at risk forhaving acne, hirsutism, alopecia, benign prostatic hyperplasia, ovariancysts, polycystic ovary disease, precocious puberty, spinal and bulbarmuscular atrophy, or age-related macular degeneration. Diagnosticmethods for various cancers, such as prostate cancer, breast cancer,ovarian cancer, salivary gland carcinoma, or endometrial cancer, anddiagnostic methods for acne, hirsutism, alopecia, benign prostatichyperplasia, ovarian cysts, polycystic ovary disease, precociouspuberty, spinal and bulbar muscular atrophy, or age-related maculardegeneration and the clinical delineation of cancer, such as prostatecancer, breast cancer, ovarian cancer, salivary gland carcinoma, orendometrial cancer, diagnoses and the clinical delineation of acne,hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts,polycystic ovary disease, precocious puberty, spinal and bulbar muscularatrophy, or age-related macular degeneration are known to those ofordinary skill in the art.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances can or can not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical can or can not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent can be water, in whichcase the solvate can be a hydrate. Alternatively, the solvent can be anorganic solvent. Thus, the compounds of the present invention can existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention can be truesolvates, while in other cases, the compound of the invention can merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“An “effective amount” refers to a therapeutically effective amount or aprophylactically effective amount. A “therapeutically effective amount”refers to an amount effective, at dosages and for periods of timenecessary, to achieve the desired therapeutic result, such as reducedtumor size, increased life span or increased life expectancy. Atherapeutically effective amount of a compound can vary according tofactors such as the disease state, age, sex, and weight of the subject,and the ability of the compound to elicit a desired response in thesubject. Dosage regimens can be adjusted to provide the optimumtherapeutic response. A therapeutically effective amount is also one inwhich any toxic or detrimental effects of the compound are outweighed bythe therapeutically beneficial effects. A “prophylactically effectiveamount” refers to an amount effective, at dosages and for periods oftime necessary, to achieve the desired prophylactic result, such assmaller tumors, increased life span, increased life expectancy orprevention of the progression of prostate cancer to acastration-resistant form. Typically, a prophylactic dose is used insubjects prior to or at an earlier stage of disease, so that aprophylactically effective amount can be less than a therapeuticallyeffective amount.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or

(iv) relieving the symptoms resulting from the disease or condition,i.e., relieving pain without addressing the underlying disease orcondition. As used herein, the terms “disease” and “condition” can beused interchangeably or can be different in that the particular maladyor condition can not have a known causative agent (so that etiology hasnot yet been worked out) and it is therefore not yet recognized as adisease but only as an undesirable condition or syndrome, wherein a moreor less specific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts can contain one or more asymmetric centers and can thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that canbe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms whether or not they are specifically depicted herein. Opticallyactive (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers can beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, for example, chromatography and fractionalcrystallization. Conventional techniques for the preparation/isolationof individual enantiomers include chiral synthesis from a suitableoptically pure precursor or resolution of the racemate (or the racemateof a salt or derivative) using, for example, chiral high pressure liquidchromatography (HPLC). When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using the ACD/NameVersion 9.07 software program, ChemDraw Ultra Version 11.0.1 and/orChemDraw Ultra Version 14.0 software naming program (CambridgeSoft). Forcomplex chemical names employed herein, a substituent group is namedbefore the group to which it attaches. For example, cyclopropylethylcomprises an ethyl backbone with cyclopropyl substituent. Except asdescribed below, all bonds are identified in the chemical structurediagrams herein, except for some carbon atoms, which are assumed to bebonded to sufficient hydrogen atoms to complete the valency.

Throughout the present specification, the terms “about” and/or“approximately” can be used in conjunction with numerical values and/orranges. The term “about” is understood to mean those values near to arecited value. For example, “about 40 [units]” can mean within ±25% of40 (e.g., from 30 to 50), within ±20%, ±15%, ±10%, ±9%, ±8%, ±7%, ±6%,±5%, ±4%, +3%, ±2%, +1%, less than +1%, or any other value or range ofvalues therein or therebelow. Furthermore, the phrases “less than about[a value]” or “greater than about [a value]” should be understood inview of the definition of the term “about” provided herein. The terms“about” and “approximately” can be used interchangeably.

Throughout the present specification, numerical ranges are provided forcertain quantities. It is to be understood that these ranges compriseall subranges therein. Thus, the range “from 50 to 80” includes allpossible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70,etc.). Furthermore, all values within a given range can be an endpointfor the range encompassed thereby (e.g., the range 50-80 includes theranges with endpoints such as 55-80, 50-75, etc.).

II. Compounds and Pharmaceutical Compositions

As noted above, certain embodiments of the present invention aredirected to compounds useful for treatment of various cancers, includingvarious types of prostate cancers. While not wishing to be bound bytheory, it is believed that binding of the compounds to the androgenreceptor (for example at the N-terminal domain) can contribute to theactivity of the disclosed compounds. The compounds of the presentinvention include novel heteroaryl, aryl, heterocyclyl, or carbocyclylgroups (i.e., R³ in Formula I) which impart improved properties to thecompounds compared to compounds lacking the described R³ moiety. Forexample, the improved properties include improved drug-like propertiessuch as improved activity (e.g., androgen receptor (AR) modulation),longer half-life (e.g., in vivo); decreased toxicity; better solubility,improved formulation, better bioavailability, better pharmacokineticprofile; reduction in unwanted metabolites and the like.

In one embodiment the invention includes compounds which form covalentbonds with the androgen receptor (AR) (e.g., at the N-terminal domain),thus resulting in irreversible (or substantially irreversible)inhibition of the same. In this regard, the certain compounds of thepresent invention are designed to include functional groups capable offorming covalent bonds with a nucleophile under certain in vivoconditions. For example, in some embodiments the reactivity of compoundsof the present invention is such that they will not substantially reactwith various nucleophiles (e.g., glutathione) when the compounds arefree in solution. However, when the free mobility of the compounds isrestricted, and an appropriate nucleophile is brought into closeproximity to the compound, for example when the compounds associatewith, or bind to, the androgen receptor, the compounds are capable offorming covalent bonds with certain nucleophiles (e.g., thiols).

The present invention includes all compounds which have the abovedescribed properties (i.e., binding to androgen receptor (AR)). In oneembodiment, the present invention is directed to a compound having astructure of Formula I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein:

X is —O—, —S(O)₀₋₂—, —C(═O)—, —C(OR⁵)₂—, —C(OR⁵)(OC(═O)R¹³)—, —C(R⁸R⁹)—,—C(═CR⁸R⁹)—, —N(R⁹)—, —N(COR⁹)—, —CHNR⁸R⁹—, —C(═NR⁹)—, —C(═NOR⁵)—,—C(═N—NHR⁵)—;

R¹ and R² are each independently H, hydroxyl, —O-heterocyclyl, or—OC(═O)R¹³;

R³ is —N₃, aryl, carbocyclyl, heteroaryl or heterocyclyl which areoptionally substituted with one or more R⁶;

R⁵ is each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl;

R⁶ is each independently selected from the group consisting of H, F, Cl,Br, I, ¹²³I, hydroxyl, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ alkoxy, C₆-C₁₂ aryl, wherein each R⁶ is optionally substitutedwith one or more of halogen, ¹²³I, ¹⁸F, hydroxyl, —OS(O)₂-aryl, C₁-C₆alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

R⁸ and R⁹ are each independently H, halogen, —S(O)₀₋₂R⁵, C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, aralkyl, C₁-C₁₀ acyl, or —NR⁵R⁵,or R⁸ and R⁹ can join to form a unsubstituted or substituted mono-, bi-,or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbonatoms;

R^(11a), R^(11b), R^(11c) and R^(11d) are each independently H, F, Cl,Br, I, ¹²³I, hydroxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;—OR⁵, —OC(═O)R¹³, C₁-C₁₀ acyl, —S(O)₀₋₂R⁵, —NO₂, —CN, —NH₂, —NHR⁵, or—N(R⁵)₂;

R¹³ is each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

n¹ and n² are each independently 0, 1, or 2; and

n³ is 0, 1, 2, 3, 4, or 5.

Accordingly, certain embodiments of the present invention are directedto compounds that bind to the AR NTD and are useful for imaging oftumors with splice variants using SPECT and/or methods of modulating ARNTD activity. Other embodiments are directed to compound and methodsuseful for imaging and/or treating benign prostate conditions ordiseases. In one embodiment, the present disclosure provides a compoundhaving a structure of Formula I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein:

X is —O—, —S(O)₀₋₂—, —C(═O)—, —C(OR⁵)₂—, —C(OR⁵)(OC(═O)R¹³)—, —C(R₈R⁹)—,—C(═CR⁸R⁹)—, —N(R⁹)—, —N(COR⁹)—, —CHNR⁸R⁹—, —C(═NR⁹)—, —C(═NOR₅)—,—C(═N—NHR⁵)—;

R¹ and R² are each independently H, hydroxyl, —O-heterocyclyl, or—OC(═O)R¹³;

R³ is —N₃, aryl, carbocyclyl, heteroaryl or heterocyclyl which areoptionally substituted with one or more R⁶.

R₅ is each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl;

R⁶ is each independently selected from the group consisting of H, F, Cl,Br, I, ¹²³I, hydroxyl, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ alkoxy, C₆-C₁₂ aryl, wherein each R⁶ is optionally substitutedwith one or more of halogen, ¹²³I, ¹⁸F, hydroxyl, —OS(O)₂-aryl, C₁-C₆alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

R⁸ and R⁹ are each independently H, halogen, —S(O)₀₋₂R⁵, C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, aralkyl, C₁-C₁₀ acyl, or —NR⁵R⁵,or R⁸ and R⁹ can join to form a unsubstituted or substituted mono-, bi-,or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbonatoms;

R^(11a), R^(11b), R^(11c) and R^(11d) are each independently H, F, Cl,Br, I, ¹²³I, hydroxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;—OR⁵, —OC(═O)R¹³, C₁-C₁₀ acyl, —S(O)₀₋₂R⁵, —NO₂, —CN, —NH₂, —NHR⁵, or—N(R⁵)₂;

R¹³ is each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

n¹ and n² are each independently 0, 1, or 2; and

n³ is 0, 1, 2, 3, 4, or 5.

In various embodiments, different stereoisomers of the compound ofstructure (I) are provided, for example in some embodiments the compoundhas one of the following structures (Ia), (Ib), (Ic) or (Id):

In still other embodiments, the compound has one of the followingstructures (Ie), (If), (Ig) or (Ih):

In some embodiments, X is —O—. In other embodiments, X is —S(O)₀₋₂—. Insome embodiments, X is —C(═O)—. In one embodiment, X is —C(OR⁵)₂—. Inone embodiment, X is —C(OR₅)(OC(═O)R¹³)—. In some embodiments, X is—C(R⁸R⁹)—. In some embodiments, X is —C(═CR⁸R⁹)—. In other embodiments,X is —N(R⁹)—. In one embodiment, X is —N(COR⁹)—. In one embodiment, X is—CHNR₈R⁹—. In another embodiment, X is —C(═NR⁹)—. In some embodiments, Xis —C(═NOR⁵)—. In other embodiments, X is —C(═N—NHR⁵)—.

In some embodiments, X is —C(R⁸R⁹)— wherein R⁸ and R⁹ are eachindependently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl. Insome embodiments, X is —C(R⁸R⁹)— wherein R⁸ and R⁹ are eachindependently H or C₁-C₁₀ alkyl, In other embodiments, X is —C(R⁸R⁹)—wherein R⁸ and R⁹ are each independently C₁-C₁₀ alkyl. In someembodiments, X is —C(R⁸R⁹)— wherein R⁸ and R⁹ are each independentlyC₁-C₅ alkyl. In one embodiment, X is —C(R⁸R⁹)— wherein R⁸ and R⁹ areeach independently C₁ alkyl. In another embodiment, X is —C(R⁸R⁹)—wherein R⁸ and R⁹ are each independently a methyl.

In certain of the foregoing embodiments, R³ is 5-6 membered heteroarylor 3-7 membered heterocylyl, wherein said heteroaryl or saidheterocyclyl comprises at least one N atom in the ring.

In another embodiment, R³ is selected from the group consisting ofpyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine,imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole,triazole, isothiazole, oxazine, triazine, azepine, pyrrolidine,pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine,piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine,and tetrazine. In one embodiment R³ is selected form the groupconsisting of triazole, morpholine, thiomorpholine, pyrazole, andimidazole.

In one embodiment, R³ is substituted with at least one R⁶. In someembodiments, R³ is substituted with at least one ¹²³I, I, Br, Cl, or F.In another embodiment, R³ is substituted with at least one ¹²³I or L.

In one embodiment, R³ is substituted with at least one R⁶ which isfurther substituted with at least one ¹²³I, I, or F. In anotherembodiment, R³ is substituted with at least one R⁶ which is C₁-C₆ alkyl,and said C₁-C₆ alkyl is further substituted with at least one ¹²³I, I,or F. In some embodiments, R³ is substituted with at least one R⁶ whichis C₁-C₆ alkyl, and said C₁-C₆ alkyl is further substituted with atleast one ¹²³I. In other embodiments, R³ is substituted with at leastone R⁶ which is C₁-C₆ alkyl, and said C₁-C₆ alkyl is further substitutedwith at least one ¹⁸F.

In one embodiment, at least one of R⁵, R^(11a), R^(11b), R^(11c) andR^(11d) is I. In another embodiment, at least one of R⁵, R^(11a),R^(11b), R^(11c) and R^(11d) is ¹²³I. In some embodiments, at least oneof R⁵, R^(11a), R_(11b), R^(11c) and R^(11d) is I and at least one ofR⁵, R^(11a), R^(11b), R^(11c) and R^(11d) is ¹²³I.

In some embodiments, R¹³ is C₁-C₃ alkyl. In other embodiments, R¹³ ismethyl, ethyl, or propyl. In one embodiment, R¹³ is a methyl.

In one embodiment, n³ is 0, 1, or 2.

The compounds for use in the imaging and treatment methods describedherein. In some embodiments, the compounds comprise one F, Cl, Br, I,¹⁸F or ¹²³I substitution. For example in certain other embodiments,three of R^(11a), R^(11b), R^(11c) and R^(11d) are H, and the remainingR^(11a), R^(11b), R^(11c) or R^(11d) is F, Cl, Br, I or ¹²³I. In someembodiments, the compounds comprise two F, Cl, Br, I or ¹²³Isubstitutions on the phenyl rings (i.e., two of R^(11a), R^(11b),R^(11c) and R^(11d) are H, and the other two of R^(11a), R^(11b),R^(11c) or R^(11d) are F, Cl, Br, I or ¹²³I). In other embodiments, thecompounds comprise three F, Cl. Br, I or ¹²³I substitutions (i.e., oneof R^(11a), R^(11b), R^(11c) and R^(11d) is H, and the remainingR^(11a), R^(11b), R^(11c) or R^(11d) is F, Cl, Br, I or ¹²³I) and inother embodiments the compounds comprise four F, Cl. Br, I or ¹²³Isubstitutions (i.e., each of R^(11a), R^(11b), R^(11c) and R^(11d) areF, Cl, Br, I or ¹²³I).

In another embodiment, the compound comprise one or more F, Cl, Br, I or¹²³I substitutions for R³. In one embodiment, the compound comprise oneor more I or ¹²³I substitutions for R³.

In some embodiments, the compound comprises at least one R⁶ substituenton R³, wherein at least one R⁶ is further substituted with at least oneof ¹²³I, I, or ¹⁸F.

Favorable imaging and/or AR NTD modulating results can be obtained bysubstitution with F, Cl. Br, I or ¹²³I at any of the “R¹¹” positions. Insome of the foregoing embodiments, R^(11a) is ¹²³I. In otherembodiments, R^(11c) is ¹²³I.

In some more specific embodiments of the compound of Formula I, thecompound has one of the following structures from Table 1, or apharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

TABLE 1 Compounds No. Structure Name 1

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 1a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol1b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol1c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol1d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 2

1-chloro-3-(2-chloro-4-(2-(4-(2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol2a

(S)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 2b

(R)-1-chloro-3-(2-chloro-4-(2-(4-((S)- 2-hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 2c

(R)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 2d

(S)-1-chloro-3-(2-chloro-4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-5-iodo- 1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 3

1-(2-bromo-4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)-3-chloropropan-2-ol 3a

(R)-1-(4-(2-(3-bromo-44(5)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propan-2-ol 3b

(S)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxyrnethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propan-2-ol 3c

(R)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxyrnethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propan-2-ol 3d

(S)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propan-2-ol 4

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-5-iodo-IH-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)-2-iodophenoxy)propan-2-ol 4a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 4b

(R)-1-chloro-3-(4-(2-(4-0)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 4c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 4d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)-2-iodophenoxy)propan-2-ol 5

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 5a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 5b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 5c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 5d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol- 1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 6

1-chloro-3-(2-chloro-4-(2-(4-(2- hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 6a

(S)-1-chloro-3-(2-chloro-4-(2-(4-((R)-2-hydroxy-3-(4-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 6b

(R)-1-chloro-3-(2-chloro-4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 6c

(R)-1-chloro-3-(2-chloro-4-(2-(4-((R)-2-hydroxy-3-(4-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 6d

(S)-1-chloro-3-(2-chloro-4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 7

1-(2-bromo-4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)-3-chloropropan-2-ol 7a

(R)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propan-2-ol 7b

(S)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-bydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propan-2-ol 7c

(R)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propan-2-ol 7d

(S)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propan-2-ol 8

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 8a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 8b

(R)-1-chloro-3-(4-(2-(4-((SR)-2- hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 8c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 8d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 9

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan- 2-yl)phenoxy)propan-2-ol 9a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 9b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 9c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 9d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy- 3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 10

1-chloro-3-(2-chloro-4-(2-(4-(2- hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 10a

(S)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 10b

(R)-1-chloro-3-(2-chloro-4-(2-(4-((S)- 2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 10c

(R)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 10d

(S)-1-chloro-3-(2-chloro-4-(2-(4-((S)-2- hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 11

1-(2-bromo-4-(2-(4-(2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan- 2-yl)phenoxy)-3-chloropropan-2-ol11a

(R)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(1H-imidazol-1- yl)propan-2-ol 11b

(S)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(IH-imidazol-1- yl)propan-2-ol 11c

(R)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(1H-imidazol-1- yl)propan-2-ol 11d

(S)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(1H-imidazol-1- yl)propan-2-ol 12

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan- 2-yl)-2-iodophenoxy)propan-2-ol 12a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 12b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 12c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 12d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy- 3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 13

1-chloro-3-(4-(2-(4-(2-hydroxy-3- morpholinopropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 13a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 13b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 13c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 13d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-morpholinopropoxy)phenyl)propan- 2-yl)phenoxy)propan-2-ol 14

1-chloro-3-(2-chloro-4-(2-(4-(2- hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 14a

(S)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 14b

(R)-1-chloro-3-(2-chloro-4-(2-(4-((S)- 2-hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 14c

(R)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 14d

(S)-1-chloro-3-(2-chloro-4-(2-(4-((S)-2- hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 15

1-(2-bromo-4-(2-(4-(2-hydroxy-3- morpholinopropoxy)phenyl)propan-2-yl)phenoxy)-3-chloropropan-2-ol 15a

(R)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-morpholinopropan-2-ol 15b

(S)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-morpholinopropan-2-ol 15c

(R)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-morpholinopropan-2-ol 15d

(S)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-morpholinopropan-2-ol 16

1-chloro-3-(4-(2-(4-(2-hydroxy-3- morpholinopropoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 16a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)-2-iodophenoxy)propan-2-ol 16b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)-2-iodophenoxy)propan-2-ol 16c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)-2-iodophenoxy)propan-2-ol 16d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-morpholinopropoxy)phenyl)propan- 2-yl)-2-iodophenoxy)propan-2-ol 17

1-chloro-3-(4-(2-(4-(2-hydroxy-3- thiomorpholinopropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 17a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)phenoxy)propan-2-ol 17b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)phenoxy)propan-2-ol 17c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)phenoxy)propan-2-ol 17d

(S)-1-chloro-3-(4-(2-(4-((S)- 2-hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)phenoxy)propan-2-ol 18

1-chloro-3-(2-chloro-4-(2-(4-(2- hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)phenoxy)propan-2-ol 18a

(S)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)phenoxy)propan-2-ol 18b

(R)-1-chloro-3-(2-chloro-4-(2-(4-((S)- 2-hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)phenoxy)propan-2-ol 18c

(R)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)phenoxy)propan-2-ol 18d

(S)-1-chloro-3-(2-chloro-4-(2-(4-((S)-2- hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)phenoxy)propan-2-ol 19

1-(2-bromo-4-(2-(4-(2-hydroxy-3- thiomorpholinopropoxy)phenyl)propan-2-yl)phenoxy)-3-chloropropan-2-ol 19a

(R)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-thiomorpholinopropan- 2-ol 19b

(S)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-thiomorpholinopropan- 2-ol 19c

(R)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-thiomorpholinopropan- 2-ol 19d

(S)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-thiomorpholinopropan- 2-ol 20

1-chloro-3-(4-(2-(4-(2-hydroxy-3- thiomorpholinopropoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 20a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)-2-iodophenoxy-)propan-2-ol20b

(R)-1-chloro-3-(4-(2-(4-((RS)-2- hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)-2-iodophenoxy)propan-2-ol 20c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)-2-iodophenoxy)propan-2-ol 20d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-thiomorpholinopropoxy)phenyl)propan- 2-yl)-2-iodophenoxy)propan-2-ol 21

1-chloro-3-(4-(2-(4-(2-hydroxy-3- (piperazin-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 21a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 21b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 21c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 21d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy- 3-(piperazin-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 22

1-chloro-3-(2-chloro-4-(2-(4-(2- hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 22a

(5)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 22b

(R)-1-chloro-3-(2-chloro-4-(2-(4-((S)- 2-hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 22c

(R)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 22d

(S)-1-chloro-3-(2-chloro-4-(2-(4-((S)-2- hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 23

1-(2-bromo-4-(2-(4-(2-hydroxy-3- (piperazin-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)-3-chloropropan-2-ol 23a

(R)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(piperazin-1-yl)propan- 2-ol 23b

(S)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(piperazin-1-yl)propan- 2-ol 23c

(R)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(piperazin-1-yl)propan- 2-ol 23d

(5)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(piperazin-1-yl)propan- 2-ol 24

1-chloro-3-(4-(2-(4-(2-hydroxy-3- (piperazin-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 24a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 24b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propart-2-yl)-2- iodophenoxy)propan-2-ol 24c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 24d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy- 3-(piperazin-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 25

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(5- (hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 25a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol25b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol25c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol25d

(S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 26

1-chloro-3-(2-chloro-4-(2-(4-(2- hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol26a

(S)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-l- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 26b

(R)-1-chloro-3-(2-chloro-4-(2-(((S)- 2-hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 26c

(R)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 26d

(S)-1-chloro-3-(2-chloro-4-(2-(4-((S)-2-hydroxy-3-(5-(hydroxymethyl)-4-iodo- 1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 27

1-(2-bromo-4-(2-(4-(2-hydroxy-3-(5- (hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)-3-chloropropan-2-ol27a

(R)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxyrnethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propan-2-ol 27b

(5)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propan-2-ol 27c

(R)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propan-2-ol 27d

(S)-1-(4-(2-(3-bromo-4-((5)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propan-2-ol 28

1-chloro-3-(4-(2-(4-(2-hydroxy-3 -(5- (hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)-2-iodophenoxy)propan-2-ol 28a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazo1-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 28b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-l- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 28c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-l- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 28d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)-2-iodophenoxy)propan-2-ol 29

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(5- (hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 29a

(5)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 29b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 29c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 29d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol- 1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 30

1-chloro-3-(2-chloro-4-(2-(4-(2- hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 30a

(S)-1-chloro-3-(2-chloro-4-(2-(4-((R)-2-hydroxy-3-(5-(hydroxymethyl)-1H- 1,2,3-triazol-l-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 30b

(R)-1-chloro-3-(2-chloro-4-(2-(4-((S)-2-hydroxy-3-(5-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 30c

(R)-1-chloro-3-(2-chloro-4-(2-(4-((R)-2-hydroxy-3-(5-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 30d

(S)-1-chloro-3-(2-chloro-4-(2-(4-((S)-2-hydroxy-3-(5-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 31

1-(2-bromo-4-(2-(4-(2-hydroxy-3-(5- (hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)-3-chloropropan-2-ol 31a

(R)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propan-2-ol 31b

(S)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propan-2-ol 31c

(R)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propan-2-ol 31d

(5)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxymethyl)-1H- 1,2,3-triazol-1-yl)propan-2-ol 32

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(5- (hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 32a

(5)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 32b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 32c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxyrnethyl)-1H-1,2,3-triazol-l- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 32d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol

In some more specific embodiments of the compound of Formula I, thecompound has one of the following structures, or a pharmaceuticallyacceptable salt, tautomer, or stereoisomer thereof including all 4distinct stereoisomers e.g., (S,R), (R,S), (R,R), and (S,S):

In some more specific embodiments of the compound of Formula I, thecompound has one of the following structures from Table 2, or apharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

TABLE 2 ¹²³I Compounds No. Structure Name 33

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 33a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 33b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 33c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-IH-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 33d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 34

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)-3-(iodo- ¹²³I)phenyl)propan-2-yl)phenoxy)propan-2-ol 34a

(5)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)-3- (iodo-¹²³I)phenyl)propan-2-yl)phenoxy)propan-2-ol 34b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)-3- (iodo-¹²³I)phenyl)propan-2-yl)phenoxy)propan-2-ol 34c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)-3- (iodo-¹²³I)phenyl)propan-2-yl)phenoxy)propan-2-ol 34d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3- triazol-1-yl)propoxy)-3-(iodo-¹²³I)phenyl)propan-2- yl)phenoxy)propan-2-ol 35

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 35a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 35b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 35c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-IH-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 35d

(S)-1-chloro-3-(4-(2-(4-((5)-2-hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H- 1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 36

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1-yl)propoxy)-3- iodophenyl)propan-2-yl)phenoxy)propan-2-ol 36a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)-3-iodophenyl)propan-2-yl)phenoxy)propan-2-ol 36b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)-3-iodophenyl)propan-2-yl)phenoxy)propan-2-ol 36c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)-3-iodophenyl)propan-2-yl)phenoxy)propan-2-ol 36d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H- 1,2,3-triazol-1-yl)propoxy)-3-iodophenyl)propan-2- yl)phenoxy)propan-2-ol 37

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 37a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 37b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 37c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 37d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H- 1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 38

1-chloro-3-(2-chloro-4-(2-(4-(2- hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 38a

(S)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 38b

(R)-1-chloro-3-(2-chloro-4-(2-(4-((S)- 2-hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 38c

(R)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 38d

(S)-1-chloro-3-(2-chloro-4-(2-(4-((5)-2- hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 39

1-(2-bromo-4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)-3-chloropropan-2-ol 39a

(R)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-5- (iodo-¹²³I)-1H-1,2,3-triazol-1-yl)propan-2-ol 39b

(S)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-5- (iodo-¹²³I)-1H-1,2,3-triazol-1-yl)propan-2-ol 39c

(R)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-5- (iodo-¹²³I)-1H-1,2,3-triazol-1-yl)propan-2-ol 39d

(S)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-5- (iodo-¹²³I)-1H-1,2,3-triazol-1-yl)propan-2-ol 40

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(4- (hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 40a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 40b

(R)-1-chloro-3-(4-(2-(4-((S-2- hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 40c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 40d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 41

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 41a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 41b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 41c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 41d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy- 3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 42

1-chloro-3-(4-(2-(4-(2-hydroxy-3- morpholinopropoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 42a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol42b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol42c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-morpholinopropoxy)phenyl)propan-2- yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol42d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-morpholinopropoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 43

1-chloro-3-(4-(2-(4-(2-hydroxy-3- thiomorpholinopropoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 43a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-thiomorpholinopropoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 43b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-thiomorpholinopropoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 43c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-thiomorpholinopropoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 43d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-thiomorpholinopropoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 44

1-chloro-3-(4-(2-(4-(2-hydroxy-3- (piperazin-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 44a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 44b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 44c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(piperazin-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 44d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy- 3-(piperazin-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 45

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(5- (hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 45a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 45b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 45c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 45d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H- 1,2,3-triazol-1-yl)propoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 46

1-chloro-3-(2-chloro-4-(2-(4-(2- hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 46a

(S)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 46b

(R)-1-chloro-3-(2-chloro-4-(2-(4-((S)- 2-hydroxy-3-(5-(hydroxymethyl)-4-(iodo-123I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 46c

(R)-1-chloro-3-(2-chloro-4-(2-(4-((R)- 2-hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 46d

(S)-1-chloro-3-(2-chloro-4-(2-(4-((S)-2- hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 47

1-(2-bromo-4-(2-(4-(2-hydroxy-3-(5- (hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)phenoxy)-3-chloropropan-2-ol 47a

(R)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxymethyl)-4- (iodo-¹²³I)-1H-1,2,3-triazol-1-yl)propan-2-ol 47b

(S)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxymethyl)-4- (iodo-¹²³I)-1H-1,2,3-triazol-1-yl)propan-2-ol 47c

(R)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxymethyl)-4- (iodo-¹²³I)-1H-1,2,3-triazol-1-yl)propan-2-ol 47d

(S)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(5-(hydroxymethyl)-4- (iodo-¹²³I)-1H-1,2,3-triazol-1-yl)propan-2-ol 48

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(5- (hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 48a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 48b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 48c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol 48d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H- 1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2- iodophenoxy)propan-2-ol 49

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(5- (hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 49a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 49b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 49c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 49d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 50

1-chloro-3-(4-(2-(4-(2-hydroxy-3-(5- (hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol 50a

(S)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 50b

(R)-1-chloro-3-(4-(2-(4-((S)-2- hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 50c

(R)-1-chloro-3-(4-(2-(4-((R)-2- hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propoxy)phenyl)propan-2-yl)-2-(iodo-¹²³I)phenoxy)propan-2-ol 50d

(S)-1-chloro-3-(4-(2-(4-((S)-2-hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2- (iodo-¹²³I)phenoxy)propan-2-ol

In some embodiments of the compound of Formula I, or a pharmaceuticallyacceptable salt, tautomer, or stereoisomer thereof including all 4distinct stereoisomers e.g., (S,R), (R,S), (R,R), and (S,S), has one ofthe following structures:

In some embodiments of the compound of Formula I, the compound has oneof the following structures from Table 3, or a pharmaceuticallyacceptable salt, tautomer, or stereoisomer thereof:

TABLE 3 ¹⁸F Compounds No. Structure Name 51

1-chloro-3-(4-(2-(4-(3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol-1-yl)-2- hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol 51a

(S)-1-chloro-3-(4-(2-(4-((R)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 51b

(R)-1-chloro-3-(4-(2-(4-((S)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 51c

(R)-1-chloro-3-(4-(2-(4-((R)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 51d

(S)-1-chloro-3-(4-(2-(4-((S)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 52

1-chloro-3-(2-chloro-4-(2-(4-(3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 52a

(S)-1-chloro-3-(2-chloro-4-(2-(4-((R)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3- triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 52b

(R)-1-chloro-3-(2-chloro-4-(2-(4-((S)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3- triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 52c

(R)-1-chloro-3-(2-chloro-4-(2-(4-((R)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3- triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 52d

(S)-1-chloro-3-(2-chloro-4-(2-(4-((S)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3- triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 53

1-(2-bromo-4-(2-(4-(3-(4-((fluoro- ¹⁸F)methyl)-1H-1,2,3-triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)-3-chloropropan-2-ol 53a

(R)-1-(4-(2-(3-bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-((fluoro-¹⁸F)methyl)- 1H-1,2,3-triazol-1-yl)propan-2-ol53b

(S)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-((fluoro-¹⁸F)methyl)- 1H-1,2,3-triazol-1-yl)propan-2-ol53c

(R)-1-(4-(2-(3-bromo-4-((R)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-((fluoro-¹⁸F)methyl)- 1H-1,2,3-triazol-1-yl)propan-2-ol53d

(S)-1-(4-(2-(3 -bromo-4-((S)-3-chloro- 2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-((fluoro-¹⁸F)methyl)- 1H-1,2,3-triazol-1-yl)propan-2-ol54

1-chloro-3-(4-(2-(4-(3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2-yl)- 2-iodophenoxy)propan-2-ol 54a

(S)-1-chloro-3-(4-(2-(4-((R)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2-yl)- 2-iodophenoxy)propan-2-ol 54b

(R)-1-chloro-3-(4-(2-(4-((S)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2-yl)- 2-iodophenoxy)propan-2-ol 54c

(R)-1-chloro-3-(4-(2-(4-((R)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2-yl)- 2-iodophenoxy)propan-2-ol 54d

(S)-1-chloro-3-(4-(2-(4-((S)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2-yl)- 2-iodophenoxy)propan-2-ol 55

1-chloro-3-(2-fluoro-4-(2-(4-(3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 55a

(S)-1-chloro-3-(2-fluoro-4-(2-(4-((R)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3- triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 55b

(R)-1-chloro-3-(2-fluoro-4-(2-(4-((S)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3- triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 55c

(R)-1-chloro-3-(2-fluoro-4-(2-(4-((R)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3- triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 55d

(S)-1-chloro-3-(2-fluoro-4-(2-(4-((S)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3- triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2- yl)phenoxy)propan-2-ol 56

1-chloro-3-(4-(2-(4-(3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol-1-yl)-2-hydroxypropoxy)phcnyl)propan-2-yl)- 2-methylphenoxy)propan-2-ol 56a

(S)-1-chloro-3-(4-(2-(4-((R)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2-yl)- 2-methylphenoxy)propan-2-ol 56b

(R)-1-chloro-3-(4-(2-(4-((S)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2-yl)- 2-methylphenoxy)propan-2-ol 56c

(R)-1-chloro-3-(4-(2-(4-((R)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2-yl)- 2-methylphenoxy)propan-2-ol 56d

(S)-1-chloro-3-(4-(2-(4-((S)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol- 1-yl)-2-hydroxypropoxy)phenyl)propan-2-yl)- 2-methylphenoxy)propan-2-ol

In some embodiments of the compound of Formula I, the compound has oneof the following structures, or a pharmaceutically acceptable salt,tautomer, or stereoisomer thereof including all 4 distinct stereoisomerse.g., (S,R), (R,S), (R,R), and (S,S):

wherein R^(11c) is H, Cl, Br, I, F, or C₁-C₆ alkyl.

In some embodiments of the compound of Formula I, the compound has oneof the following structures, or a pharmaceutically acceptable saltthereof:

wherein R^(11c) is H, Cl, Br, I, F, or C₁-C₆ alkyl.

In one embodiment, the present invention is directed to a pharmaceuticalcomposition, comprising a compound having a structure of Formula I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein:

X is —O—, —S(O)₀₋₂—, —C(═O)—, —C(OR⁵)₂—, —C(OR⁵)(OC(═O)R¹³)—, —C(R⁸R⁹)—,—C(═CR⁸R⁹)—, —N(R⁹)—, —N(COR⁹)—, —CHNR⁸R⁹—, —C(═NR⁹)—, —C(═NOR⁵)—,—C(═N—NHR⁵)—;

R¹ and R² are each independently H, hydroxyl, —O-heterocyclyl, or—OC(═O)R¹³;

R³ is —N₃, aryl, carbocyclyl, heteroaryl or heterocyclyl which areoptionally substituted with one or more R⁶;

R⁵ is each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl;

R⁶ is each independently selected from the group consisting of H, F, Cl,Br, I, ¹²³I, hydroxyl, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ alkoxy, C₆-C₁₂ aryl, wherein each R⁶ is optionally substitutedwith one or more of halogen, ¹²³I, ¹⁸F, hydroxyl, —OS(O)₂-aryl, C₁-C₆alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

R⁸ and R⁹ are each independently H, halogen, —S(O)₀₋₂R⁵, C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, aralkyl, C₁-C₁₀ acyl, or —NR⁵R⁵,or R⁸ and R⁹ can join to form a unsubstituted or substituted mono-, bi-,or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbonatoms;

R^(11a), R^(11b), R^(11c) and R^(11d) are each independently H, F, Cl,Br, I, ¹²³I, hydroxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;—OR⁵, —OC(═O)R¹³, C₁-C₁₀ acyl, —S(O)₀₋₂R⁵, —NO₂, —CN, —NH₂, —NHR⁵, or—N(R⁵)₂;

R¹³ is each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

n¹ and n² are each independently 0, 1, or 2; and

n³ is 0, 1, 2, 3, 4, or 5.

In some embodiment, the pharmaceutical composition comprising a compoundhaving a structure of Formula I further comprises a pharmaceuticallyacceptable carrier. In another embodiment, the pharmaceuticalcomposition comprising a compound having a structure of Formula Ifurther comprises an additional therapeutic agent. In one embodiment,the pharmaceutical composition comprising a compound having a structureof Formula I further comprises a pharmaceutically acceptable carrier andan additional therapeutic agent.

In another embodiment, the pharmaceutical composition comprising acompound having a structure of Formula I further comprises an additionaltherapeutic agent which is for treating prostate cancer, breast cancer,ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss,acne, hirsutism, ovarian cysts, polycystic ovary disease, precociouspuberty, spinal and bulbar muscular atrophy, or age-related maculardegeneration.

Accordingly, one embodiment comprises the use of the disclosed compoundsin combination therapy with one or more currently-used or experimentalpharmacological therapies which are utilized for treating the abovedisease states irrespective of the biological mechanism of action ofsuch pharmacological therapies, including without limitationpharmacological therapies which directly or indirectly inhibit theandrogen receptor, pharmacological therapies which are cyto-toxic innature, and pharmacological therapies which interfere with thebiological production or function of androgen (hereinafter, an“additional therapeutic agent”). By “combination therapy” is meant theadministration of any one or more of a compound of Formula I with one ormore of another therapeutic agent to the same patient such that theirpharmacological effects are contemporaneous with one another, or if notcontemporaneous, that their effects are synergistic with one anothereven though dosed sequentially rather than contemporaneously.

Such administration includes without limitation dosing of one or more ofa compound of Formula I and one or more of the additional therapeuticagent(s) as separate agents without any comingling prior to dosing, aswell as formulations which include one or more other androgen-blockingtherapeutic agents mixed with one or more compound of Formula I as apre-mixed formulation. Administration of the compound(s) of Formula I incombination with the additional therapeutic agents for treatment of theabove disease states also includes dosing by any dosing method includingwithout limitation, intravenous delivery, oral delivery,intra-peritoneal delivery, intra-muscular delivery, or intra-tumoraldelivery.

In another aspect of the present disclosure, the one or more of theadditional therapeutic agents can be administered to the patient beforeadministration of the compound(s) of Formula I. In another embodiment,the compound(s) of Formula I can be co-administered with one or more ofthe additional therapeutic agents. In yet another aspect, the one ormore additional therapeutic agents can be administered to the patientafter administration of the compound(s) of Formula I.

The ratio of the doses of compound(s) of Formula I to that of the one ormore additional therapeutic agents can be about 1:1 or can vary, e.g.,about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about8:1, about 9:1, about 10:1, about 1:2, about 1:3, about 1:4, about 1:5,about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, and can bevaried accordingly to achieve the optimal therapeutic benefit.

The compound(s) of Formula I that are combined with the one or moreadditional therapeutic agents for improved treatment of the abovedisease states can comprise, but are not limited to any compound havinga structure of Formula I, including those compounds shown in Tables 1,2, or 3.

The additional therapeutic agents include without limitation anypharmacological agent which is currently approved by the FDA in the U.S.(or elsewhere by any other regulatory body) for use as pharmacologicaltreatment of any of the above disease states, or which is currentlybeing used experimentally as part of a clinical trial program thatrelates to the above disease states. Non-limiting examples of the OtherPharmacological Agents comprise, without limitation: the chemical entityknown as ODM-201 (also known as BAY1841788) and related compounds, whichappears to bind to the AR and blocks its cellular function, and iscurrently in clinical development as a treatment for prostate cancer);the chemical entity known as enzalutamide(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide)and related compounds, which appears to be a blocker of the androgenreceptor (AR) LBD and a FDA-approved treatment for prostate cancer; thechemical entity known as Galeterone and related compounds which appearsto be a blocker of the androgen receptor (AR) LBD, and a CYP17 lyaseinhibitor, and also appears to decrease overall androgen receptor levelsin prostate cancer cells. Galeterone is currently in development as atreatment for prostate cancer; the chemical entity known as ARN-509(4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide)and related compounds which appears to be a blocker of the androgenreceptor (AR) LBD and is currently in development as a treatment forprostate cancer; the chemical entity known as abiraterone (or CB-7630;(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol),and related molecules, which appears to block the production of androgenand FDA-approved treatment for prostate cancer; the chemical entityknown as bicalutamide(N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide)and related compounds, which appears to be a blocker of the androgenreceptor (AR) LBD and which is currently used to treat prostate cancer,the chemical entity known as nilutamide(5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione) and related compounds, which appears to be ablocker of the AR LBD and which is currently used to treat prostatecancer, the chemical entity known as flutamide(2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide) and relatedcompounds, which appears to be a blocker of the androgen receptor (AR)LBD and which is currently used to treat prostate cancer, the chemicalentities known as cyproterone acetate(6-chloro-1β,2β-dihydro-17-hydroxy-3′H-cyclopropa[1,2]pregna-4,6-diene-3,20-dione)and related compounds, which appears to be a blocker of the androgenreceptor (AR) LBD and which is currently used to treat prostate cancer,the chemical entity known as docetaxel (Taxotere;1,7β,10β-trihydroxy-9-oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl 4-acetate2-benzoate13-{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate})and related compounds, which appears to be a cytotoxic antimicrotubuleagent and is currently used in combination with prednisone to treatprostate cancer, the chemical entity known as Bevacizumab (Avastin), amonoclonal antibody that recognizes and blocks vascular endothelialgrowth factor A (VEGF-A) and can be used to treat prostate cancer, thechemical entity known as OSU-HDAC42((S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide), andrelated compounds, which appears to act as a histone deacetylaseinhibitor, and is currently being developed as a treatment for prostatecancer, the chemical entity known as VITAXIN which appears to be amonoclonal antibody against the vascular integrin αvβ3 to preventangiogenesis, and which can be used to treat prostate cancer, thechemical entity known as sunitumib(N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide)and related compounds, which appears to inhibit multiple receptortyrosine kinases (RTKs) and can be used for treatment of prostatecancer, the chemical entity known as ZD-4054(N-(3-Methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridin-3-sulfonamid)and related compounds, which appears to block the edta receptor andwhich can be used for treatment of prostate cancer; the chemical entityknown as Cabazitaxel (XRP-6258), and related compounds, which appears tobe a cytotoxic microtubule inhibitor, and which is currently used totreat prostate cancer; the chemical entity known as MDX-010(Ipilimumab), a fully human monoclonal antibody that binds to and blocksthe activity of CTLA-4 which is currently in development as animmunotherapeutic agent for treatment of prostate cancer; the chemicalentity known as OGX 427 which appears to target HSP27 as an antisenseagent, and which is currently in development for treatment of prostatecancer; the chemical entity known as OGX 011 which appears to targetclusterin as an antisense agent, and which is currently in developmentas a treatment for prostate cancer; the chemical entity known asfinasteride (Proscar, Propecia;N-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamide),and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone, and can be used to treatprostate cancer; the chemical entity known as dutasteride (Avodart; 5α,17β)-N-{2,5 bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide) and related molecules,which appears to be a 5-alpha reductase inhibitor that reduces levels ofdihydrotestosterone, and can be used in the treatment of prostatecancer; the chemical entity known as turosteride((4aR,4bS,6aS,7S,9aS,9bS,11aR)-1,4a,6a-trimethyl-2-oxo-N-(propan-2-yl)-N-(propan-2ylcarbamoyl)hexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide), andrelated molecules, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and can be used in thetreatment of prostate cancer; the chemical entity known as bexlosteride(LY-191,704;(4aS,10bR)-8-chloro-4-methyl-1,2,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one),and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and can be used in thetreatment of prostate cancer; the chemical entity known as izonsteride(LY-320,236;(4aR,10bR)-8-[(4-ethyl-1,3-benzothiazol-2-yl)sulfanyl]-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one)and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and can be used for thetreatment of prostate cancer; the chemical entity known as FCE 28260 andrelated compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and can be used for thetreatment of prostate cancer; the chemical entity known as SKF105,111,and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and can be used for treatmentof prostate cancer.

Accordingly, in some embodiments, the pharmaceutical compositioncomprising a compound having a structure of Formula I further comprisesan additional therapeutic agent selected form the group consisting ofenzalutamide, Galeterone, ARN-509; abiraterone, bicalutamide,nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab(Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel(XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride,dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260,SKF105,111, ODM-201, radium 233, or related compounds thereof.

In some embodiments, compounds of Formula I which result in unstablestructures and/or unsatisfied valences are not included within the scopeof the invention.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition comprising any of the foregoing compounds of Formula I and apharmaceutically acceptable carrier.

Compounds as described herein can be in the free form or in the form ofa salt thereof. In some embodiments, compounds as described herein canbe in the form of a pharmaceutically acceptable salt, which are known inthe art (Berge et al., J. Pharm. Sci. 1977, 66, 1). Pharmaceuticallyacceptable salt as used herein includes, for example, salts that havethe desired pharmacological activity of the parent compound (salts whichretain the biological effectiveness and/or properties of the parentcompound and which are not biologically and/or otherwise undesirable).Compounds as described herein having one or more functional groupscapable of forming a salt can be, for example, formed as apharmaceutically acceptable salt. Compounds containing one or more basicfunctional groups can be capable of forming a pharmaceuticallyacceptable salt with, for example, a pharmaceutically acceptable organicor inorganic acid. Pharmaceutically acceptable salts can be derivedfrom, for example, and without limitation, acetic acid, adipic acid,alginic acid, aspartic acid, ascorbic acid, benzoic acid,benzenesulfonic acid, butyric acid, cinnamic acid, citric acid,camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid,diethylacetic acid, digluconic acid, dodecylsulfonic acid,ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid,gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid,heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid,hydriodic acid, 2-hydroxyethanesulfonic acid, isonicotinic acid, lacticacid, malic acid, maleic acid, malonic acid, mandelic acid,methanesulfonic acid, 2-napthalenesulfonic acid, naphthalenedisulphonicacid, p-toluenesulfonic acid, nicotinic acid, nitric acid, oxalic acid,pamoic acid, pectinic acid, 3-phenylpropionic acid, phosphoric acid,picric acid, pimelic acid, pivalic acid, propionic acid, pyruvic acid,salicylic acid, succinic acid, sulfuric acid, sulfamic acid, tartaricacid, thiocyanic acid or undecanoic acid. Compounds containing one ormore acidic functional groups can be capable of forming pharmaceuticallyacceptable salts with a pharmaceutically acceptable base, for example,and without limitation, inorganic bases based on alkaline metals oralkaline earth metals or organic bases such as primary amine compounds,secondary amine compounds, tertiary amine compounds, quaternary aminecompounds, substituted amines, naturally occurring substituted amines,cyclic amines or basic ion-exchange resins. Pharmaceutically acceptablesalts can be derived from, for example, and without limitation, ahydroxide, carbonate, or bicarbonate of a pharmaceutically acceptablemetal cation such as ammonium, sodium, potassium, lithium, calcium,magnesium, iron, zinc, copper, manganese or aluminum, ammonia,benzathine, meglumine, methylamine, dimethylamine, trimethylamine,ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine,tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,glucamine, methylglucamine, theobromine, purines, piperazine,piperidine, procaine, N-ethylpiperidine, theobromine,tetramethylammonium compounds, tetraethylammonium compounds, pyridine,N,N-dimethylaniline, N-methylpiperidine, morpholine, N-methylmorpholine,N-ethylmorpholine, dicyclohexylamine, dibenzylamine,N,N-dibenzylphenethylamine, I-ephenamine, N,N-dibenzylethylenediamine orpolyamine resins. In some embodiments, compounds as described herein cancontain both acidic and basic groups and can be in the form of innersalts or zwitterions, for example, and without limitation, betaines.Salts as described herein can be prepared by conventional processesknown to a person skilled in the art, for example, and withoutlimitation, by reacting the free form with an organic acid or inorganicacid or base, or by anion exchange or cation exchange from other salts.Those skilled in the art will appreciate that preparation of salts canoccur in situ during isolation and purification of the compounds orpreparation of salts can occur by separately reacting an isolated andpurified compound.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, polymorphs, isomeric forms) as described herein canbe in the solvent addition form, for example, solvates. Solvates containeither stoichiometric or non-stoichiometric amounts of a solvent inphysical association the compound or salt thereof. The solvent can be,for example, and without limitation, a pharmaceutically acceptablesolvent. For example, hydrates are formed when the solvent is water oralcoholates are formed when the solvent is an alcohol.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, solvates, isomeric forms) as described herein caninclude crystalline and amorphous forms, for example, polymorphs,pseudopolymorphs, conformational polymorphs, amorphous forms, or acombination thereof. Polymorphs include different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability and/or solubility. Those skilled in the art willappreciate that various factors including recrystallization solvent,rate of crystallization and storage temperature can cause a singlecrystal form to dominate.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, solvates, polymorphs) as described herein includeisomers such as geometrical isomers, optical isomers based on asymmetriccarbon, stereoisomers, tautomers, individual enantiomers, individualdiastereomers, racemates, diastereomeric mixtures and combinationsthereof, and are not limited by the description of the formulaillustrated for the sake of convenience.

III. Methods

The present compounds find use in any number of methods. For example, insome embodiments the compounds are useful in methods for modulatingandrogen receptor (AR). Accordingly, in one embodiment, the presentdisclosure provides the use of any one of the foregoing compounds ofFormula I for modulating androgen receptor (AR) activity. For example insome embodiments, modulating androgen receptor (AR) activity is in amammalian cell. Modulating androgen receptor (AR) can be in a subject inneed thereof (e.g., a mammalian subject) and for treatment of any of thedescribed conditions or diseases.

In other embodiments, modulating androgen receptor (AR) activity is fortreatment of at least one indication selected from the group consistingof: prostate cancer, breast cancer, ovarian cancer, endometrial cancer,salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts,polycystic ovary disease, precocious puberty, spinal and bulbar muscularatrophy, age related macular degeneration, and combinations thereof. Forexample in some embodiments, the indication is prostate cancer. In otherembodiments, the prostate cancer is castration resistant prostate cancer(also referred to as hormone refractory, androgen-independent, androgendeprivation resistant, androgen ablation resistant, androgendepletion-independent, castration-recurrent, anti-androgen-recurrent).While in other embodiments, the prostate cancer is androgen dependentprostate cancer. In other embodiments, the spinal and bulbar muscularatrophy is Kennedy's disease.

In some embodiments, compounds as described herein can be administeredto a subject. In one embodiment, the present invention is directed to amethod of treating castration resistant prostate cancer comprisingadministering a pharmaceutical composition comprising a compound havinga structure of Formula I. In some embodiments, the present invention isdirected to a method of treating androgen-dependent prostate cancercomprising administering a pharmaceutical composition comprising acompound having a structure of Formula I. In other embodiments, thepresent invention is directed to a method of treatingandrogen-independent prostate cancer comprising administering apharmaceutical composition comprising a compound having a structure ofFormula I.

In other embodiments, the present disclosure provides a method ofmodulating androgen receptor (AR) activity, the method comprisingadministering any one of the foregoing compounds of Formula I,pharmaceutically acceptable salt thereof, or pharmaceutical compositionof Formula I as described herein (including compositions comprising acompound of Formula I and an additional therapeutic agent), to a subject(e.g., mammal) in need thereof. In some embodiments, modulating androgenreceptor (AR) activity is in a mammalian cell. In other embodiments,modulating androgen receptor (AR) activity is in a mammal. In oneembodiment, modulating androgen receptor (AR) activity is in a human.

The modulating androgen receptor (AR) activity can be for inhibiting ARN-terminal domain activity. The modulating androgen receptor (AR)activity can be for inhibiting androgen receptor (AR) activity. Themodulating can be in vivo. The modulating androgen receptor (AR)activity can be for treatment of at least one indication selected fromthe group consisting of: prostate cancer, breast cancer, ovarian cancer,endometrial cancer, salivary gland carcinoma, hair loss, acne,hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty,spinal and bulbar muscular atrophy (e.g., Kennedy's disease), and agerelated macular degeneration. The indication can be prostate cancer. Theprostate cancer can be castration-resistant prostate cancer. Theprostate cancer can be androgen dependent prostate cancer.

In accordance with another embodiment, there is provided a use of thecompounds of Formula I, pharmaceutically acceptable salt thereof, orpharmaceutical composition of Formula I as described herein forpreparation of a medicament for modulating androgen receptor (AR).

Alternatively, in one embodiment, a method of modulating androgenreceptor activity, comprising administering Formula I, pharmaceuticallyacceptable salt thereof, or pharmaceutical composition of Formula I asdescribed herein, is provided. In some embodiments, the administrationcan be to a mammal. In other embodiments, the administering can be to amammal in need thereof and in an effective amount for the treatment ofat least one indication selected from the group consisting of: prostatecancer, breast cancer, ovarian cancer, endometrial cancer, salivarygland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycysticovary disease, precocious puberty, spinal and bulbar muscular atrophy(e.g., Kennedy's disease), age related macular degeneration, andcombinations thereof.

As noted above, the presently disclosed compounds can find utility in anumber of medical imaging applications, including imaging of theprostate. Many currently available imaging agents tend to accumulate inthe bladder, which decreases their effectiveness as imaging toolsspecifically for the prostate. While not wishing to be bound by theory,the present applicants believe the disclosed compounds are unexpectedlyeffective for imaging of the prostate due to their ability to accumulatein the prostate, rather than the bladder, allowing the prostate gland tobe seen. Accordingly, the compounds can be used in methods for imagingthe prostate, for example to image benign prostate diseases. In otherembodiments, the compounds can be used in methods to image cancerousprostate diseases, such as tumors of the prostate.

Androgen ablation therapy causes a temporary reduction in prostatecancer tumor burden, but the malignancy will begin to grow again in theabsence of testicular androgens to form castrate resistant prostatecancer (CRPC). A rising titer of serum prostate-specific antigen (PSA)after androgen ablation therapy indicates biochemical failure, theemergence of CRPC, and re-initiation of an androgen receptor (AR)transcription program. Most patients succumb to CRPC within two years ofbiochemical failure.

AR is a transcription factor and a validated target for prostate cancertherapy. Current therapies include androgen ablation and administrationof antiandrogens. Most CRPC is suspected to be AR-dependent. AR hasdistinct functional domains that include the C-terminus ligand-bindingdomain (LBD), a DNA-binding domain (DBD), and an amino-terminal domain(NTD). AR NTD contains the activation function-1 (AF-1) that contributesmost of the activity to the AR. Recently, splice variants of the AR thatlack the LBD have been reported in prostate cancer cell lines (VCaP and22Rv1), and in CRPC tissues. To date more than 20 splice variants of ARhave been detected. Splice variants V7 and V567es are clinicallyrelevant with levels of expression correlated to poor survival and CRPC.AR V567es is solely expressed in 20% of metastases. Abirateroneresistance is associated with expression of AR splice variants,Enzalutamide also increases levels of expression of these constitutivelyactive AR splice variants. These splice variants lack LBD and therebywould not be inhibited by current therapies that target the AR LBD suchas antiandrogens or androgen ablation therapy. A single patient withadvanced prostate cancer can have many lesions throughout the body andskeleton and each tumor can have differing levels of expression of AR.

Biopsy of metastatic tumors in a patient to determine AR species isneither widely accessible nor feasible to sample tumors in a patientthat can have multiple metastases. Thus it is essential to developapproaches to detect the expression of all AR species for the molecularclassification of tumors based on the level and extent of expression ofAR splice variants, or other AR species that cannot be detected using animaging agent that interacts with the LBD, to identify patients withpotentially aggressive disease and poor prognosis, or to identifypatients that will not respond to hormone therapies that target the ARLBD. Accordingly, certain embodiments of the present invention provide aAR NTD-targeted molecular imaging probe (e.g., compound of formula I)which can be used to monitor response to therapy and provide insightinto the role of AR in resistance mechanisms.

One current approach to image AR in prostate cancer uses positronemission tomography (PET) with 16β-[¹⁸F]-fluoro-5α dihydrotestosterone(¹⁸F-FDHT) that binds to AR LBD. Unfortunately this imaging agent cannotdetect splice variants lacking LBD. In some embodiments, the inventionemploys sequential imaging with ¹⁸F-FDHT to detect full-length AR andgamma radiation emitting probes to specifically detect the AR NTD whichwould be the sum of both full-length AR and variant AR. In otherembodiments, the invention employs sequential imaging with two differentPET imaging agents to detects only full-length AR and another tospecifically detect the AR NTD which would be the sum of bothfull-length AR and variant AR. Together these data reveal patients withtumors that express variant AR (NTD of variant plus full-length ARdetected with NTD isotope minus full-length AR detected with ¹⁸F-FDHT).By using sequential imaging, a discordant distribution or discordantlevel of uptake between ¹⁸F-FDHT and a radiolabeled compound of thisinvention (i.e., compound of Formula I) indicates the presence ofoverexpression of splice variants lacking the LBD.

As described above, radioactive ¹⁸F labeled compounds have found use asimaging agents not only to image AR in prostate cancer but for imagingvarious organs and various tumors. Similarly, radioactive ¹²³I labeledcompounds have been known for the use as imaging agents. In oneembodiment, the compounds of the present disclosure comprise at leastone ¹⁸F and/or ¹²³I.

In one embodiment, the present invention is directed to a method ofimaging cancer by administering a compound having a structure of FormulaI to a subject. In another embodiment, the present invention is directedto a method of imaging cancer by administering a pharmaceuticalcomposition comprising a compound having a structure of Formula I to asubject.

In some embodiment, the method of imaging cancer by administering acompound having a structure of Formula I or a pharmaceutical compositioncomprising Formula I to a subject and detecting the presence or absenceof cancer by use of SPECT or PET. In other embodiments, the method ofimaging cancer by administering a compound having a structure of FormulaI to a subject and the method identifies the presence or absence of atumor. In one embodiment, the method of imaging cancer by administeringa compound having a structure of Formula I to a subject and the methodidentifies the location of a tumor. In one embodiment, the method ofimaging cancer by administering a compound having a structure of FormulaI to a subject and the method identifies a presence of a prostatecancer. In other embodiments, the prostate cancer is androgen-dependentprostate cancer. In some embodiments, the subject is a mammal such as ahuman.

In some other embodiments, the method is useful for detecting thepresence of AR splice variants or other AR species that cannot bedetected by imaging agents that interact with the AR LBD (i.e.,mutations, truncations). Without wishing to be bound by any particulartheory, since the present compounds bind to the AR N-terminal domain(NTD), even mutants or variants which lack the AR LBD can be imagedemploying the present compounds. Thus, the present methods can be usefulfor detecting AR species, including mutants and variants, which lack theLBD or have LBD mutations, but do comprise the AR NTD. In otherembodiments the method detects the presence or overexpression of ARsplice variants lacking the ligand binding domain. For example, themethod can include sequential imaging with ¹⁸F-FDHT and a compound ofthe invention and a discordant distribution or discordant level ofuptake between ¹⁸F-FDHT and the compound of the invention indicates thepresence or overexpression of splice variants lacking the ligand bindingdomain.

In other embodiments, the compounds of the invention are used in singlephoton emission computed tomography methods to monitor a patient'sresponse to therapy. In other embodiments, the methods comprise use of acompound of the invention to detect the AR NTD.

In accordance with a further embodiment, the method of imaging a canceris by administering a compound as described anywhere herein. In oneembodiment, the method of imaging a cancer is by administering acompound represented in Table 2, Table 3 or a pharmaceuticallyacceptable salt, tautomer, or stereoisomer thereof. In some embodiments,the imaging is in a mammalian cell. In one embodiment, the imaging is ina mammal. In other embodiments, the imaging is in a human patient.

The administering and imaging can be to a mammal in need of diagnosis ofat least one indication selected from the group consisting of: prostatecancer, breast cancer, ovarian cancer, endometrial cancer, salivarygland carcinoma, benign prostatic hyperplasia, hair loss, acne,hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty,spinal and bulbar muscular atrophy (e.g., Kennedy's disease), andage-related macular degeneration. The imaging can be for imaging ARsplice variants, mutants or other AR species which comprise the AR NTD.

In some embodiments, the compounds as described herein orpharmaceutically acceptable salts thereof can be used for imaging anddiagnosis of at least one indication selected from the group consistingof: prostate cancer, breast cancer, ovarian cancer, endometrial cancer,salivary gland carcinoma, benign prostatic hyperplasia, hair loss, acne,hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty,spinal and bulbar muscular atrophy, and age-related maculardegeneration. In some embodiments, the compounds as described herein oracceptable salts thereof above can be used in the preparation of amedicament or a composition for imaging the prostate, for example forimaging benign prostate conditions or for imaging prostate cancer in asubject in need of such imaging (for example for diagnosis and/orlocation of prostate tumors).

In some embodiments, pharmaceutical compositions useful in modulatingandrogen receptor (AR) activity or useful for imaging, in accordancewith this invention can comprise a salt of such a compound, preferably apharmaceutically or physiologically acceptable salt. Pharmaceuticalpreparations will typically comprise one or more carriers, excipients ordiluents acceptable for the mode of administration of the preparation,be it by injection, inhalation, topical administration, lavage, or othermodes suitable for the selected treatment. Suitable carriers, excipientsor diluents are those known in the art for use in such modes ofadministration.

Suitable pharmaceutical compositions can be formulated by means known inthe art and their mode of administration and dose determined by theskilled practitioner. For parenteral administration, a compound can bedissolved in sterile water or saline or a pharmaceutically acceptablevehicle used for administration of non-water soluble compounds such asthose used for vitamin K. For enteral administration, the compound canbe administered in a tablet, capsule or dissolved in liquid form. Thetablet or capsule can be enteric coated, or in a formulation forsustained release. Many suitable formulations are known, including,polymeric or protein microparticles encapsulating a compound to bereleased, ointments, pastes, gels, hydrogels, or solutions which can beused topically or locally to administer a compound. A sustained releasepatch or implant can be employed to provide release over a prolongedperiod of time. Many techniques known to one of skill in the art aredescribed in Remington: the Science & Practice of Pharmacy by AlfonsoGennaro, 20^(th) ed., Lippencott Williams & Wilkins, (2000).Formulations for parenteral administration can, for example, containexcipients, polyalkylene glycols such as polyethylene glycol, oils ofvegetable origin, or hydrogenated naphthalenes. Biocompatible,biodegradable lactide polymer, lactide/glycolide copolymer, orpolyoxyethylene-polyoxypropylene copolymers can be used to control therelease of the compounds. Other potentially useful parenteral deliverysystems for modulatory compounds include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, andliposomes. Formulations for inhalation can contain excipients, forexample, lactose, or can be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or can beoily solutions for administration in the form of nasal drops, or as agel.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound as described herein, and an additionaltherapeutic agent and/or a pharmaceutically acceptable carrier. In someembodiments, the additional therapeutic agent is for treating prostatecancer, breast cancer, ovarian cancer, endometrial cancer, salivarygland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycysticovary disease, precocious puberty, spinal and bulbar muscular atrophy orage related macular degeneration. In other embodiments, the additionaltherapeutic agent is enzalutamide, galeterone, ARN-509, ODN-201abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate,docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib,ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011,finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE28260, SKF105,111 ODM-201, or related compounds thereof.

Compounds described herein can also be used in assays and for researchpurposes. Definitions used include ligand dependent activation of theandrogen receptor (AR) by androgens such as dihydrotestosterone (DHT) orthe synthetic androgen (R1881) used for research purposes.Ligand-independent activation of the androgen receptor (AR) refers totransactivation of the full length androgen receptor (AR) in the absenceof androgen (ligand) by, for example, stimulation of the cAMP dependentprotein kinase (PKA) pathway with forskolin (FSK). Some compounds andcompositions of this invention can inhibit both FSK and androgen (e.g.R1881, a synthetic androgen) induction of ARE luciferase (ARE-luc).Constitutive activity of the androgen receptor (AR) refers to splicevariants lacking the androgen receptor (AR) ligand-binding domain. Suchcompounds can block a mechanism that is common to both ligand dependentand ligand independent activation of the androgen receptor (AR), as wellas constitutively active splice variants of the androgen receptor (AR)that lack ligand-binding domain. This could involve any step inactivation of the androgen receptor (AR) including dissociation ofheatshock proteins, essential posttranslational modifications (e.g.,acetylation, phosphorylation), nuclear translocation, protein-proteininteractions, formation of the transcriptional complex, release of corepressors, and/or increased degradation. Some compounds andcompositions of this invention can inhibit ligand-only activity and caninterfere with a mechanism specific to ligand dependent activation(e.g., accessibility of the ligand binding domain (LBD) to androgen).Numerous disorders in addition to prostate cancer involve the androgenaxis (e.g., acne, hirsutism, alopecia, benign prostatic hyperplasia) andcompounds interfering with this mechanism can be used to treat suchconditions. Some compounds and compositions of this invention can onlyinhibit FSK induction and can be specific inhibitors to ligandindependent activation of the androgen receptor (AR). These compoundsand compositions can interfere with the cascade of events that normallyoccur with FSK and/or PKA activity or any downstream effects that canplay a role on the androgen receptor (AR) (e.g. FSK increases MAPKactivity which has a potent effect on androgen receptor (AR) activity).Examples can include an inhibitor of cAMP and or PKA or other kinases.Some compounds and compositions of this invention can induce basallevels of activity of the AR (no androgen or stimulation of the PKApathway). Some compounds and compositions of this invention can increaseinduction by R1881 or FSK. Such compounds and compositions can stimulatetranscription or transactivation of the AR. Some compounds andcompositions of this invention can inhibit activity of the androgenreceptor. Interleukin 6 (IL 6) also causes ligand independent activationof the androgen receptor (AR) in LNCaP cells and can be used in additionto FSK.

Compounds or pharmaceutical compositions in accordance with thisinvention or for use in this invention can be administered by means of amedical device or appliance such as an implant, graft, prosthesis,stent, etc. Also, implants can be devised which are intended to containand release such compounds or compositions. An example would be animplant made of a polymeric material adapted to release the compoundover a period of time.

It is to be noted that dosage values can vary with the exact imagingprotocol. For any particular subject, specific dosage regimens can beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the compositions. Dosage ranges set forth herein are exemplary onlyand do not limit the dosage ranges that can be selected by medicalpractitioners. The amount of active compound(s) in the composition canvary according to factors such as the disease state, age, sex, andweight of the subject. Dosage regimens can be adjusted to provide theoptimum imaging result. For example, a single bolus can be administered,several divided doses can be administered over time or the dose can beproportionally reduced or increased as indicated by the imaging results.It can be advantageous to formulate parenteral compositions in dosageunit form for ease of administration and uniformity of dosage.

In general, compounds of the invention should be used without causingsubstantial toxicity. Toxicity of the compounds of the invention can bedetermined using standard techniques, for example, by testing in cellcultures or experimental animals and determining the therapeutic index,i.e., the ratio between the LD50 (the dose lethal to 50% of thepopulation) and the LD100 (the dose lethal to 100% of the population).In some circumstances, such as in severe disease conditions, substantialexcesses of the compositions can be administered for therapeuticeffects. Some compounds of this invention can be toxic at someconcentrations. Titration studies can be used to determine toxic andnon-toxic concentrations. Toxicity can be evaluated by examining aparticular compound's or composition's specificity across cell linesusing PC3 or DU145 cells as possible negative controls since these cellsdo not express functional AR. Animal studies can be used to provide anindication if the compound has any effects on other tissues. Systemictherapy that targets the AR will not likely cause major problems toother tissues since antiandrogens and androgen insensitivity syndromeare not fatal.

Compounds for use in the present invention can be obtained from medicalsources or modified using known methodologies from naturally occurringcompounds. In addition, methods of preparing or synthesizing compoundsof the present invention will be understood by a person of skill in theart having reference to known chemical synthesis principles. Forexample, Auzou et al 1974 European Journal of Medicinal Chemistry 9(5),548-554 describes suitable synthetic procedures that can be consideredand suitably adapted for preparing compounds of any one of the compoundsof structure (I) as set out above. Other references that can be helpfulinclude: Debasish Das, Jyh-Fu Lee and Soofin Cheng “Sulfonic acidfunctionalized mesoporous MCM-41 silica as a convenient catalyst forBisphenol-A synthesis” Chemical Communications, (2001) 2178-2179; U.S.Pat. No. 2,571,217 Davis, Orris L.; Knight, Horace S.; Skinner, John R.(Shell Development Co.) “Halohydrin ethers of phenols.” (1951); andRokicki, G.; Pawlicki, J.; Kuran, W. “Reactions of4-chloromethyl-1,3-dioxolan-2-one with phenols as a new route to polyolsand cyclic carbonates.” Journal fuer Praktische Chemie (Leipzig) (1985)327, 718-722.

In some embodiments, compounds and all different forms thereof asdescribed herein can be used, for example, and without limitation, incombination with other treatment methods for at least one indicationselected from the group consisting of: prostate cancer, breast cancer,ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss,acne, hirsutism, ovarian cysts, polycystic ovary disease, precociouspuberty, spinal and bulbar muscular atrophy, and age related maculardegeneration. For example, compounds and all their different forms asdescribed herein can be used as neoadjuvant (prior), adjunctive(during), and/or adjuvant (after) therapy with surgery, radiation(brachytherapy or external beam), or other therapies (eg. HIFU), and incombination with chemotherapies, androgen ablation, antiandrogens or anyother therapeutic approach.

In an exemplary embodiment for imaging the prostate, a dose of thedisclosed compounds in solution (typically 5 to 10 millicuries or 200 to400 MBq) is typically injected rapidly into a saline drip running into avein, in a patient. Then, the patient is placed in the SPECT for aseries of one or more scans which can take from 20 minutes to as long asan hour (often, only about one quarter of the body length can be imagedat a time). Methods for SPECT scanning are well known in the art.

The compounds described herein can be used for in vivo or in vitroresearch uses (i.e. non-clinical) to investigate the mechanisms oforphan and nuclear receptors (including steroid receptors such asandrogen receptor (AR)). Furthermore, these compounds can be usedindividually or as part of a kit for in vivo or in vitro research toinvestigate signal transduction pathways and/or the activation of orphanand nuclear receptors using recombinant proteins, cells maintained inculture, and/or animal models.

For example, exemplary compounds of the present invention can beprepared with reference to the following General Reaction Scheme I:

It should be noted that, although General Reaction Scheme I depicts acertain stereochemistiy in the products, one skilled in the art wouldrecognize that other stereoisomers can be synthesized by using startingmaterials of different stereochemistry, such as for step a and step d.

Referring to General Reaction Scheme I,(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol can toslyated under basicconditions as shown in step a. In step b, tosly group(p-toulenesulfonate) can be displaced with bisphenol derivatives underbasic conditions. Optionally, in step c, the bisphenol derivative ishalogenated on the phenyl ring. In step d, the unreacted phenol portionundergoes another elimination reaction to afford a stereospecificbisphenol derivative with an epoxide on one side and a protected diol onthe other. In step e, epoxide is opened using CeCl₃.7H₂O and the diol isdeprotected in situ. In step f, primary alcohol is selectively tosylatedthen in step g, the tosyl group is displaced with an azide using sodiumazide. Lastly, Click chemistry provides triazole containing products insteps h and i. Tosyl leaving groups have been found to be particularlyuseful in the synthesis outlined in General Scheme I.

The radioactive iodine moiety (¹²³I) can be installed by step c with anappropriate iodinating reagent, for example Na¹²³I and a suitableoxidant (e.g., NaClO). It should be noted that, although GeneralReaction Scheme I depicts iodination at only one position, othercompounds of structure (I) with ¹²³I at different positions and/ormultiple ¹²³I substitutions can be prepared according to analogousmethods known to those of ordinary skill in the art. Further, ¹²³I atomscan be introduced via any number of reagents, and iodination is notlimited to those methods depicted or described above. Methods for suchiodination are well known in the art. Methodologies for preparation ofspecific exemplary compounds of structure I are described in more detailin the following examples.

One skilled in the art will recognize that variations to the order ofthe steps and reagents discussed in reference to the above GeneralSynthetic Schemes I are possible. For example, epoxidation can precededioxalone formation.

In addition, protecting group strategies can be employed for preparationof the compounds disclosed herein. Such strategies are well known tothose of skill in the art. Exemplary protecting groups and relatedstrategies are disclosed in Greene's Protective Groups in OrganicSynthesis, Wiley-InterScience; 4 edition (Oct. 30, 2006), which ishereby incorporated by reference in its entirety. In certainembodiments, a protecting group is used to mask an alcohol moiety whileperforming other chemical transformations. After removal of theprotecting group, the free hydroxyl is obtained. Such protecting groupsand strategies are well known in the art.

Various alternative embodiments and examples of the invention aredescribed herein. These embodiments and examples are illustrative andshould not be construed as limiting the scope of the invention. Thefollowing examples are provided for purposes of illustration, notlimitation.

EXAMPLES

All non-aqueous reactions were performed in flame-dried round bottomedflasks. The flasks were fitted with rubber septa and reactions wereconducted under a positive pressure of argon unless otherwise specified.Stainless steel syringes were used to transfer air- andmoisture-sensitive liquids. Flash column chromatography was performed asdescribed by Still et al. (Still, W. C.; Kahn, M.; Mitra, A. J. Org.Chem. 1978, 43, 2923) using 230-400 mesh silica gel. Thin-layerchromatography was performed using aluminum plates pre-coated with 0.25mm 230-400 mesh silica gel impregnated with a fluorescent indicator (254nm). Thin-layer chromatography plates were visualized by exposure toultraviolet light and a “Seebach” staining solution (700 mL water, 10.5g Cerium (IV) sulphate tetrahydrate, 15.0 g molybdato phosphoric acid,17.5 g sulphuric acid) followed by heating (˜1 min) with a heating gun(˜250° C.). Organic solutions were concentrated on Büchi R-114 rotatoryevaporators at reduced pressure (15-30 torr, house vacuum) at 25-40° C.

Commercial regents and solvents were used as received. All solvents usedfor extraction and chromatography were HPLC grade. Normal-phase Si gelSep Paks™ were purchased from waters, Inc. Thin-layer chromatographyplates were Kieselgel 60F₂₅₄. All synthetic reagents were purchased fromSigma Aldrich and Fisher Scientific Canada.

Example 1 Synthesis of(S)-1-(4-(2-(3-bromo-4-((R)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propan-2-ol(1a) and(S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol(25a)

Compound i-H (X═H)

p-Toluenesulfonyl chloride (˜1.5 equiv) was added portionwise over aperiod of approximately 10 min to a solution of(R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol(1 equiv) and DMAP (˜0.01 equiv) in anhydrous pyridine (˜1M) in a waterbath. The resulting solution was stirred at room temperature. Thepyridine was removed under reduced pressure, and the residue was dilutedwith ethyl acetate, washed subsequently with water (×2), cold aqueous 1M HCl, saturated NaHCO₃ and water. The organic layer was dried overMg₂SO₄, filtered and concentrated the crude product. The crude productwas purified by column chromatography (eluent: ethyl acetate/hexane) toafford Compound i-H. ¹H NMR and ¹³C NMR spectra are shown in FIGS. 1 and2, respectively.

Compound ii-H (X═H)

Sodium azide (˜1.5 equiv) was added to a solution of Compound i-H (1equiv) in anhydrous dimethyl formamide, at room temperature. Thereaction mixture was heated at 60° C. Once the reaction is complete, anyexcess sodium azide was quenched using common laboratory procedures. Theproduct was extracted with ethyl acetate (×3). The organic layer waswashed with saturated NaHCO₃ and water, dried over anhydrous magnesiumsulfate, filtered, and then concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel (eluent: ethyl acetate/hexane) to provide Compound ii-H. ¹H NMR and¹³C NMR spectra are shown in FIGS. 3 and 4, respectively.

Compounds 1a and 25a

CuI and NIS was added to a solution of Compound ii-H (1 equiv) andpropargyl alcohol (˜1.5 equiv) in DMF and triethylamine. The reactionmixture is stirred at room temperature. Once the reaction was complete,any excess reagents were quenched using common laboratory procedures.The product was extracted with ethyl acetate (×3). The organic layer waswashed with saturated NaHCO₃ and water, dried over anhydrous magnesiumsulfate, filtered, and then concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel (eluent: ethyl acetate/hexane) to provide Compound 1a and Compound25a.

Compound 1a: ¹H NMR and ¹³C NMR spectra are shown in FIGS. 5 and 6respectively. MS (ES+): m/z 624.3 [M+Na]⁺.

Compound 25a: ¹H NMR and ¹³C NMR spectra are shown in FIGS. 7 and 8,respectively. MS (ES+): m/z 624.3 [M+Na]⁺.

Example 2 Synthesis of(S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol(4a) and(S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol(28a)

Compounds 4a and 28a

Compound 4a and Compound 28a were synthesized according to Example 1from(R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)-3-iodophenyl)propan-2-yl)phenoxy)propane-1,2-diol.

Compound i-I (X═I): ¹H NMR and ¹³C NMR spectra are shown in FIGS. 9 and10, respectively.

Compound ii-I (X═I): ¹H NMR and ¹³C NMR spectra are shown in FIGS. 11and 12, respectively.

Compound 4a: ¹H NMR and ¹³C NMR spectra are shown in FIGS. 13 and 14,respectively.

Compound 28a: ¹H NMR and ¹³C NMR spectra are shown in FIGS. 15 and 16,respectively.

Example 3 Synthesis of(S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(4-(hydroxymethyl)-5-(iodo-¹²³I)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol(33a) and(S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(5-(hydroxymethyl)-4-(iodo-¹²³I)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol(41a)

Compounds 37a and 45a

CuCl₂ and Na¹²³I are added to a solution of Compound ii-H (1 equiv) andpropargyl alcohol (˜1.5 equiv) in acetonitrile and triethylamine. Thereaction mixture is stirred at room temperature. Once the reaction iscomplete, any excess reagents are quenched using common laboratoryprocedures. The product is extracted with ethyl acetate (×3). Theorganic layer is washed with saturated NaHCO₃ and water, dried overanhydrous magnesium sulfate, filtered, and then concentrated underreduced pressure. The resulting residue is purified by flash columnchromatography on silica gel (eluent: ethyl acetate/hexane) to provideCompound 37a and Compound 45a.

Example 4 Synthesis of(S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol(5a) and(S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol(29a)

Compounds 5a and 29a

CuCl₂ and NIS is added to a solution of Compound ii-H (1 equiv) andpropargyl alcohol (˜1.5 equiv) in DMF and triethylamine. The reactionmixture is stirred at room temperature. Once the reaction is complete,any excess reagents are quenched using common laboratory procedures. Theproduct is extracted with ethyl acetate (×3). The organic layer iswashed with saturated NaHCO₃ and water, dried over anhydrous magnesiumsulfate, filtered, and then concentrated under reduced pressure. Theresulting residue is purified by flash column chromatography on silicagel (eluent: ethyl acetate/hexane) to provide Compound 5a and Compound29a.

Example 5 Synthesis of1-chloro-3-(4-(2-(4-(2-hydroxy-3-morpholinopropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol(13)

Compound 13

To a solution of2,2′-(((propane-2,2-diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(oxirane)(1.0 equiv) and morpholine (˜1 equiv) in acetonitrile/water (9:1) wasadded CeCl₃.7H₂O (˜0.5 equiv) and the mixture was refluxed. Theresulting crude mixture was filtered and washed with ethyl acetate, andthe resulting suspension was concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel (eluent: ethyl acetate/hexane) to provide the title Compound 13. ¹HNMR spectrum is shown in FIGS. 17. MS (ESI+): m/z 464.3 [M]⁺.

Example 6 Synthesis of(S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-morpholinopropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol(13a)

Compound 13a

To a solution of(2R,2′R)-2,2′-(((propane-2,2-diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(oxirane)(1.0 equiv) and morpholine (˜1 equiv) in acetonitrile/water (9:1) isadded CeCl₃.7H₂O (˜0.5 equiv) and the mixture is refluxed. The resultingcrude mixture is filtered and washed with ethyl acetate, and theresulting suspension is concentrated under reduced pressure. Theresulting residue is purified by flash column chromatography on silicagel (eluent: ethyl acetate/hexane) to provide Compound 13a and Compound13b.

Example 7 Synthesis of1-chloro-3-(4-(2-(4-(2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol(9)

Compound 9

To a solution of2,2′-(((propane-2,2-diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(oxirane)(1 equiv) and 1H-imidazole (˜1 equiv) in acetonitrile/water (9:1) wereadded CeCl₃.7H₂O (˜0.5 equiv) and the mixture was refluxed. Theresulting crude mixture was filtered and washed with ethyl acetate, andthe resulting suspension was concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel (eluent: ethyl acetate/hexane) to provide Compound 9.

Example 8 Synthesis of(S)-1-chloro-3-(4-(2-(4-((R)-3-(4-((fluoro-¹⁸F)methyl)-1H-1,2,3-triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol(51a)

Compound iii-H (X═H)

p-Toluenesulfonyl chloride (˜1.5 equiv) is added portion wise over aperiod of approximately 10 min to a solution of Compound 5a (1 equiv)and TEA in DCM (˜1M) in a water bath. The resulting solution is stirredat room temperature. The solvent is removed under reduced pressure, andthe residue is diluted with ethyl acetate, washed subsequently withwater (×2), cold aqueous 1 M HCl, saturated NaHCO₃ and water. Theorganic layer was dried over Mg₂SO₄, filtered and concentrated the crudeproduct. The crude product is purified by column chromatography (eluent:ethyl acetate/hexane) to afford Compound iii-H.

Compound iv-H (X═H)

3,4-Dihydro-2H-pyran and PPTS is added to a solution of Compound iii-H(1 equiv) in DCM. The resulting solution is stirred until reaction iscomplete. The solvent is removed under reduced pressure, and the residueis diluted with ethyl acetate, washed subsequently with saturated NaHCO₃and water. The organic layer was dried over Mg₂SO₄, filtered andconcentrated the crude product. The crude product is purified by columnchromatography (eluent: ethyl acetate/hexane) to afford Compound iv-H.

Compound 51a

To a solution of Compound iv-H (1 equiv) in MeCN is added K¹⁸F andK₂CO₃, and the reaction mixture is heated at 110° C. Once the reactionis complete, concentrated HCl is added and stirred. The product isextracted with ethyl acetate, and the resulting suspension isconcentrated under reduced pressure. The resulting residue is purifiedby flash column chromatography on silica gel (eluent: ethylacetate/hexane) to provide Compound 51a.

Example 9 Compound Activity

LNCaP cells were transiently transfected with PSA (6.1 kb)-luciferasefor 24 h prior to pre-treatment with compounds of the invention (e.g.,compounds 1a, 9, 13) ranging in concentration from 62.5 ng/ml to 1.5ug/ml for 1 hour before the addition of vehicle, or synthetic androgen,R1881 (1 nM) to induce luciferase production. After 24 h of incubationwith R1881, the cells were harvested, and relative luciferase activitieswere determined. To determine the IC₅₀, treatments were normalized tothe predicted maximal activity induction (in the absence of testcompounds, vehicle only).

TABLE 4 IC₅₀ values for selected compounds (μM) with standard errorCompound Number of Trials Average IC₅₀ 1a 4  3.23 +/− 0.37 9 6  8.45 +/−3.14 13 3 12.84 +/− 1.95

Although various embodiments of the invention are disclosed herein, manyadaptations and modifications can be made within the scope of theinvention in accordance with the common general knowledge of thoseskilled in this art. Such modifications include the substitution ofknown equivalents for any aspect of the invention in order to achievethe same result in substantially the same way. Numeric ranges areinclusive of the numbers defining the range. The word “comprising” isused herein as an open-ended term, substantially equivalent to thephrase “including, but not limited to”, and the word “comprises” has acorresponding meaning. As used herein, the singular forms “a”, “an” and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a thing” includes more thanone such thing. Citation of references herein is not an admission thatsuch references are prior art to the present invention. Any prioritydocument(s) and all publications, including but not limited to patentsand patent applications, cited in this specification are incorporatedherein by reference as if each individual publication were specificallyand individually indicated to be incorporated by reference herein and asthough fully set forth herein. The invention includes all embodimentsand variations substantially as hereinbefore described and withreference to the examples and drawings.

What is claimed is:
 1. A compound having the following structure (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein: X is —O—, —S(O)₀₋₂—, —C(═O)—, —C(OR⁵)₂—, —C(OR⁵)(OC(═O)R¹³)—,—C(R⁸R⁹)—, —C(═CR⁸R⁹)—, —N(R⁹)—, —N(COR⁹)—, —CHNR⁸R⁹—, —C(═NR⁹)—,—C(═NOR⁵)—, —C(═N—NHR⁵)—; R¹ and R² are each independently H, hydroxyl,—O-heterocyclyl, or —OC(═O)R¹³; R³ is —N₃, aryl, carbocyclyl, heteroarylor heterocyclyl which are optionally substituted with one or more R⁶; R⁵is each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;R⁶ is each independently selected from the group consisting of H, F, Cl,Br, I, ¹²³I, hydroxyl, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ alkoxy, C₆-C₁₂ aryl, wherein each R⁶ is optionally substitutedwith one or more of halogen, ¹²³I, ¹⁸F, hydroxyl, —OS(O)₂-aryl, C₁-C₆alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; R⁸ and R⁹ are each independentlyH, halogen, —S(O)₀₋₂R⁵, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,aryl, aralkyl, C₁-C₁₀ acyl, or —NR⁵R⁵, or R⁸ and R⁹ can join to form aunsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle orheterocycle containing from 3 to 20 carbon atoms; R^(11a), R^(11b),R^(11c) and R^(11d) are each independently H, F, Cl, Br, I, ¹²³I,hydroxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; —OR⁵,—OC(═O)R¹³, C₁-C₁₀ acyl, —S(O)₀₋₂R⁵, —NO₂, —CN, —NH₂, —NHR⁵, or —N(R⁵)₂;R¹³ is each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;n¹ and n² are each independently 0, 1, or 2; and n³ is 0, 1, 2, 3, 4, or5.
 2. The compound of claim 1, wherein X is —C(R⁸R⁹)—.
 3. The compoundof claim 1 or 2, wherein R⁸ and R⁹ are C₁-C₁₀ alkyl.
 4. The compound ofclaim 1 or 2, wherein R⁸ and R⁹ are methyl.
 5. The compound of claim 1,wherein R³ is 5-6 membered heteroaryl or 3-7 membered heterocylyl,wherein said heteroaryl or said heterocyclyl comprises at least one Natom in the ring.
 6. The compound of claim 1, wherein R³ is selectedfrom a group consisting of pyrrole, furan, thiophene, pyrazole,pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole,oxadiazole, thiadiazole, oxazole, triazole, isothiazole, oxazine,triazine, azepine, pyrrolidine, pyrroline, imidazoline, imidazolidine,pyrazoline, pyrazolidine, piperidine, dioxane, morpholine, dithiane,thiomorpholine, piperazine, and tetrazine.
 7. The compound of claim 1,wherein R³ is substituted with at least one ¹²³I or I.
 8. The compoundof claim 1, wherein R³ is substituted with at least one R⁶, wherein atleast one R⁶ is further substituted with at least one of ¹²³I, I, or¹⁸F.
 9. The compound of claim 1, wherein at least one R⁶ is C₁-C₆ alkyl,wherein s at least one R⁶ is further substituted with at least one of¹²³I, I, or ¹⁸F.
 10. The compound of claim 1, wherein each R¹³ isindependently methyl, ethyl or propyl.
 11. The compound of claim 1,wherein each R¹³ is methyl.
 12. The compound of claim 1, wherein atleast one of R^(11a), R^(11b), R^(11c) and R^(11d) is Cl, Br, I or ¹²³I.13. The compound of claim 1, wherein at least one of R⁵, R^(11a),R^(11b), R^(11c) and R^(11d) is I; and at least one of R⁵, R^(11a),R^(11b), R^(11c) and R^(11d) is ¹²³I.
 14. The compound of claim 1,wherein n³ is 0, 1, or
 2. 15. The compound of claim 1, wherein thecompound has one of the following structures:

or a pharmaceutically acceptable salt, tautomer, or stereoisomerthereof.
 16. The compound of claim 1, wherein the compound has one ofthe following structures:

or a pharmaceutically acceptable salt, tautomer, or stereoisomerthereof.
 17. A pharmaceutical composition, comprising: a compound offormula (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein: X is —O—, —S(O)₀₋₂—, —C(═O)—, —C(OR⁵)₂—, —C(OR⁵)(OC(═O)R¹³)—,—C(R⁸R⁹)—, —C(═CR⁸R⁹)—, —N(R⁹)—, —N(COR⁹)—, —CHNR⁸R⁹—, —C(═NR⁹)—,—C(—NOR⁵)—, —C(═N—NHR⁵)—; R¹ and R² are each independently H, hydroxyl,—O-heterocyclyl, or —OC(═O)R¹³; R³ is —N₃, aryl, carbocyclyl, heteroarylor heterocyclyl which are optionally substituted with one or more R⁶; R⁵is each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;R⁶ is each independently selected from the group consisting of H, F, Cl,Br, I, ¹²³I, hydroxyl, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ alkoxy, C₆-C₁₂ aryl, wherein each R⁶ is optionally substitutedwith one or more of halogen, ¹²³I, ¹⁸F, hydroxyl, —OS(O)₂-aryl, C₁-C₆alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; R⁸ and R⁹ are each independentlyH, halogen, —S(O)₀₋₂R⁵, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,aryl, aralkyl, C₁-C₁₀ acyl, or —NR⁵R⁵, or R⁸ and R⁹ can join to form aunsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle orheterocycle containing from 3 to 20 carbon atoms; R^(11a), R^(11b),R^(11c) and R^(11d) are each independently H, F, Cl, Br, I, ¹²³I,hydroxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; —OR⁵,—OC(═O)R¹³, C₁-C₁₀ acyl, —S(O)₀₋₂R⁵, —NO₂, —CN, —NH₂, —NHR⁵, or —N(R⁵)₂;R¹³ is each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;n¹ and n² are each independently 0, 1, or 2; and n³ is 0, 1, 2, 3, 4, or5.
 18. The pharmaceutical composition of claim 17, further comprising apharmaceutically acceptable carrier.
 19. The pharmaceutical compositionof claim 17, further comprising a pharmaceutically acceptable carrierand an additional therapeutic agent.
 20. The pharmaceutical compositionof claim 19, wherein the additional therapeutic agent is for treatingprostate cancer, breast cancer, ovarian cancer, endometrial cancer,salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts,polycystic ovary disease, precocious puberty, spinal and bulbar muscularatrophy, or age-related macular degeneration.
 21. The pharmaceuticalcomposition of claim 19, wherein the additional therapeutic agent isenzalutamide, Galeterone, ARN-509; abiraterone, bicalutamide,nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab(Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel(XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride,dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260,SKF105,111, ODM-201, radium 233, or related compounds thereof.
 22. Amethod for modulating androgen receptor activity, comprising:administering a pharmaceutical composition according to claim 17 to apatient in need thereof.
 23. A method for treating a condition ordisease that is responsive to modulation of androgen receptor activity,comprising: administering a pharmaceutical composition according toclaim 17 to a patient in need thereof, wherein said condition or diseaseis selected from the group consisting of: prostate cancer, breastcancer, ovarian cancer, endometrial cancer, salivary gland carcinoma,hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease,precocious puberty, spinal and bulbar muscular atrophy, and age-relatedmacular degeneration.
 24. The method of claim 23, wherein the conditionor disease is prostate cancer.
 25. The method of claim 23, wherein thecondition or disease is castration resistant prostate cancer.
 26. Themethod of claim 23, wherein the condition or disease isandrogen-dependent prostate cancer.
 27. A method for treating acondition or disease selected from the group consisting of: prostatecancer, breast cancer, ovarian cancer, endometrial cancer, salivarygland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycysticovary disease, precocious puberty, spinal and bulbar muscular atrophy,and age-related macular degeneration, comprising: administering to apatient in need thereof a compound having the following structure (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein: X is —O—, —S(O)₀₋₂—, —C(═O)—, —C(OR⁵)₂—, —C(OR⁵)(OC(═O)R¹³)—,—C(R⁸R⁹)—, —C(═CR⁸R⁹)—, —N(R⁹)—, —N(COR⁹)—, —CHNR⁸R⁹—, —C(═NR⁹)—,—C(═NOR⁵)—, —C(═N—NHR⁵)—; R¹ and R² are each independently H, hydroxyl,—O-heterocyclyl, or —OC(═O)R¹³; R³ is —N₃, aryl, carbocyclyl, heteroarylor heterocyclyl which are optionally substituted with one or more R⁶; R⁵is each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;R⁶ is each independently selected from the group consisting of H, F, Cl,Br, I, ¹²³I, hydroxyl, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ alkoxy, C₆-C₁₂ aryl, wherein each R⁶ is optionally substitutedwith one or more of halogen, ¹²³I, ¹⁸F, hydroxyl, —OS(O)₂-aryl, C₁-C₆alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; R⁸ and R⁹ are each independentlyH, halogen, —S(O)₀₋₂R⁵, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,aryl, aralkyl, C₁-C₁₀ acyl, or —NR⁵R⁵, or R⁸ and R⁹ can join to form aunsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle orheterocycle containing from 3 to 20 carbon atoms; R^(11a), R^(11b),R^(11c) and R^(11d) are each independently H, F, Cl, Br, I, ¹²³I,hydroxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; —OR¹,—OC(═O)R¹³, C₁-C₁₀ acyl, —S(O)₀₋₂R⁵, —NO₂, —CN, —NH₂, —NHR⁵, or —N(R⁵)₂;R¹³ is each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;n¹ and n² are each independently 0, 1, or 2; and n³ is 0, 1, 2, 3, 4, or5.
 28. The method of claim 27, wherein the condition or disease isprostate cancer.
 29. The method of claim 27, wherein the condition ordisease is castration resistant prostate cancer or androgen-dependentprostate cancer.
 30. A method of imaging cancer, the method comprisingadministering a compound of claim 1 to a subject and detecting thepresence or absence of cancer by use of SPECT or PET.
 31. The method ofclaim 30, wherein the method identifies the presence or absence of atumor.
 32. The method of claim 30, wherein the method identifies thelocation of a tumor.
 33. The method of claim 30, wherein the cancer isprostate cancer.
 34. The method of claim 30, wherein the compound ofclaim 1 is selected from the group consisting of:

or a pharmaceutically acceptable salt, tautomer, or stereoisomerthereof.
 35. A method of imaging cancer, the method comprisingadministering the pharmaceutical composition of claim 17 to a subjectand detecting the presence or absence of cancer by use of SPECT or PET.36. The compound of claim 1, wherein the compound has one of thefollowing structures:

or a pharmaceutically acceptable salt, tautomer, or stereoisomerthereof; wherein R^(11c) is H, Cl, Br, I, F, or C₁-C₆ alkyl.
 37. Thecompound of claim 1, wherein the compound has one of the followingstructures:

or a pharmaceutically acceptable salt thereof; wherein R^(11c) is H, Cl,Br, I, F, or C₁-C₆ alkyl.